SARMS and method of use thereof

ABSTRACT

This invention provides SARM compounds and uses thereof in treating a variety of diseases or conditions in a subject, including, inter-alia, muscle wasting diseases and/or disorders, bone-related diseases and/or disorders, diabetes, cardiovascular disease, renal disease and others.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part Application of U.S. patentapplication Ser. No. 10/861,905 filed Jun. 7, 2004, which is aContinuation-In-Part Application of U.S. patent application Ser. No.10/371,155 filed Feb. 24, 2003, which claims the benefit of U.S.Provisional Patent Application Ser. No. 60/453,736 filed Jan. 29, 2003and U.S. Provisional Patent Application Ser. No. 60/423,381, filed Nov.4, 2002; and this application is a Continuation-In-Part Application ofU.S. patent application Ser. No. 11/723,957, filed on Mar. 22, 2007,which is a Divisional Application of U.S. patent application Ser. No.10/683,125, filed on Oct. 14, 2003, which claims the benefit of U.S.Provisional Patent Application Ser. No. 60/418,173, filed Oct. 15, 2002;and this application is a Continuation-In-Part Application of U.S.patent application Ser. No. 11/510,844, filed on Aug. 28, 2006, whichclaims the benefit of U.S. Provisional Patent Application No.60/712,390, filed Aug. 31, 2005; and this Application claims the benefitof U.S. Provisional Application Ser. No. 60/839,665, filed Aug. 24,2006, all of which are hereby incorporated by reference in theirentirety.

GOVERNMENT INTEREST STATEMENT

This invention was made in whole or in part with government supportunder grant number R01 DK598006, awarded by the National Institute ofHealth; under grant number R29 CA068096 awarded by the National CancerInstitute, National Institute of Health; under grant number R15 HD35329,awarded by the National Institute of Child Health and Human Development,National Institute of Health and under grant number R01 DK59800, awardedby the National Institute of Health. The government may have certainrights in the invention.

BACKGROUND OF THE INVENTION

The androgen receptor (“AR”) is a ligand-activated transcriptionalregulatory protein that mediates induction of male sexual developmentand function through its activity with endogenous androgens. Androgensare generally known as the male sex hormones. The androgenic hormonesare steroids which are produced in the body by the testes and the cortexof the adrenal gland or can be synthesized in the laboratory. Androgenicsteroids play an important role in many physiologic processes, includingthe development and maintenance of male sexual characteristics such asmuscle and bone mass, prostate growth, spermatogenesis, and the malehair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am. 23:857-75(1994)). The endogenous steroidal androgens include testosterone anddihydrotestosterone (“DHT”). Testosterone is the principal steroidsecreted by the testes and is the primary circulating androgen found inthe plasma of males. Testosterone is converted to DHT by the enzyme 5alpha-reductase in many peripheral tissues. DHT is thus thought to serveas the intracellular mediator for most androgen actions (Zhou, et al.,Molec. Endocrinol. 9:208-18 (1995)). Other steroidal androgens includeesters of testosterone, such as the cypionate, propionate,phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, anddecanoate esters, and other synthetic androgens such as7-Methyl-Nortestosterone (“MENT’) and its acetate ester (Sundaram etal., “7 Alpha-Methyl-Nortestosterone (MENT): The Optimal Androgen ForMale Contraception,” Ann. Med., 25:199-205 (1993) (“Sundaram”). Becausethe AR is involved in male sexual development and function, the AR is alikely target for effecting male contraception or other forms of hormonereplacement therapy.

Worldwide population growth and social awareness of family planning havestimulated a great deal of research in contraception. Contraception is adifficult subject under any circumstance. It is fraught with culturaland social stigma, religious implications, and, most certainly,significant health concerns. This situation is only exacerbated when thesubject focuses on male contraception. Despite the availability ofsuitable contraceptive devices, historically, society has looked towomen to be responsible for contraceptive decisions and theirconsequences. Although concern over sexually transmitted diseases hasmade men more aware of the need to develop safe and responsible sexualhabits, women still often bear the brunt of contraceptive choice. Womenhave a number of choices, from temporary mechanical devices such assponges and diaphragms to temporary chemical devices such asspermicides. Women also have at their disposal more permanent options,such as physical devices including IUDs and cervical caps as well asmore permanent chemical treatments such as birth control pills andsubcutaneous implants. However, to date, the only options available formen include the use of condoms and vasectomy. Condom use, however is notfavored by many men because of the reduced sexual sensitivity, theinterruption in sexual spontaneity, and the significant possibility ofpregnancy caused by breakage or misuse. Vasectomies are also notfavored. If more convenient methods of birth control were available tomen, particularly long-term methods which require no preparativeactivity immediately prior to a sexual act, such methods couldsignificantly increase the likelihood that men would take moreresponsibility for contraception.

Administration of the male sex steroids (e.g., testosterone and itsderivatives) has shown particular promise in this regard due to thecombined gonadotropin-suppressing and androgen-substituting propertiesof these compounds (Steinberger et al., “Effect of ChronicAdministration of Testosterone Enanthate on Sperm Production and PlasmaTestosterone, Follicle Stimulating Hormone, and Luteinizing HormoneLevels: A Preliminary Evaluation of a Possible Male Contraceptive,Fertility and Sterility 28:1320-28 (1977)). Chronic administration ofhigh doses of testosterone completely abolishes sperm production(azoospermia) or reduces it to a very low level (oligospermia). Thedegree of spermatogenic suppression necessary to produce infertility isnot precisely known. However, a recent report by the World HealthOrganization showed that weekly intramuscular injections of testosteroneenanthate result in azoospermia or severe oligospermia (i.e., less than3 million sperm per ml) and infertility in 98% of men receiving therapy(World Health Organization Task Force on Methods And Regulation of MaleFertility, “Contraceptive Efficacy of Testosterone-Induced Azoospermiaand Oligospermia in Normal Men,” Fertility and Sterility 65:821-29(1996)).

A variety of testosterone esters have been developed which are moreslowly absorbed after intramuscular injection and thus result in greaterandrogenic effect. Testosterone enanthate is the most widely used ofthese esters. While testosterone enanthate has been valuable in terms ofestablishing the feasibility of hormonal agents for male contraception,it has several drawbacks, including the need for weekly injections andthe presence of supraphysiologic peak levels of testosterone immediatelyfollowing intramuscular injection (Wu, “Effects of TestosteroneEnanthate in Normal Men: Experience From a Multicenter ContraceptiveEfficacy Study,” Fertility and Sterility 65:626-36 (1996)).

Bone mineral density (BMD) decreases with age in both males and females.Decreased amounts of bone mineral content (BMC) and BMD correlate withdecreased bone strength and predispose patients to fracture.

Osteoporosis is a systemic skeletal disease, characterized by low bonemass and deterioration of bone tissue, with a consequent increase inbone fragility and susceptibility to fracture. In the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most seriousconsequence of osteoporosis, with 5-20% of patients dying within oneyear, and over 50% of survivors being incapacitated. The elderly are atgreatest risk of osteoporosis, and the problem is therefore predicted toincrease significantly with the aging of the population. Worldwidefracture incidence is forecasted to increase three-fold over the next 60years, and one study estimated that there will be 4.5 million hipfractures worldwide in 2050.

Women are at greater risk of osteoporosis than men. Women experience asharp acceleration of bone loss during the five years followingmenopause. Other factors that increase the risk include smoking, alcoholabuse, a sedentary lifestyle and low calcium intake. However,osteoporosis also occurs frequently in males. It is well establishedthat the bone mineral density of males decrease with age. Decreasedamounts of bone mineral content and density correlates with decreasedbone strength, and predisposes to fracture. The molecular mechanismsunderlying the pleiotropic effects of sex-hormones in non-reproductivetissues are only beginning to be understood, but it is clear thatphysiologic concentrations of androgens and estrogens play an importantrole in maintaining bone homeostasis throughout the life-cycle.Consequently, when androgen or estrogen deprivation occurs there is aresultant increase in the rate of bone remodeling that tilts the balanceof resorption and formation to the favor of resorption that contributesto the overall loss of bone mass. In males, the natural decline insex-hormones at maturity (direct decline in androgens as well as lowerlevels of estrogens derived from peripheral aromatization of androgens)is associated with the frailty of bones. This effect is also observed inmales who have been castrated.

Muscle wasting refers to the progressive loss of muscle mass and/or tothe progressive weakening and degeneration of muscles, including theskeletal or voluntary muscles, which control movement, cardiac muscles,which control the heart (cardiomyopathics), and smooth muscles. Chronicmuscle wasting is a chronic condition (i.e. persisting over a longperiod of time) characterized by progressive loss of muscle mass,weakening and degeneration of muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by muscle protein degradation by catabolism. Proteincatabolism occurs because of an unusually high rate of proteindegradation, an unusually low rate of protein synthesis, or acombination of both. Muscle protein catabolism, whether caused by a highdegree of protein degradation or a low degree of protein synthesis,leads to a decrease in muscle mass and to muscle wasting.

Muscle wasting is associated with chronic, neurological, genetic orinfectious pathologies, diseases, illnesses or conditions. These includeMuscular Dystrophies such as Duchenne Muscular Dystrophy and MyotonicDystrophy; Muscle Atrophies such as Post-Polio Muscle Atrophy (PPMA);Cachexias such as Cardiac Cachexia, AIDS Cachexia and Cancer Cachexia,malnutrition, Leprosy, Diabetes, Renal Disease, Chronic ObstructivePulmonary Disease (COPD), Cancer, end stage Renal failure, Sarcopenia,Emphysema, Osteomalacia, HIV Infection, AIDS, and Cardiomyopathy.

In addition, other circumstances and conditions are linked to and cancause muscle wasting. These include chronic lower back pain, advancedage, central nervous system (CNS) injury, peripheral nerve injury,spinal cord injury, chemical injury, central nervous system (CNS)damage, peripheral nerve damage, spinal cord damage, chemical damage,burns, disuse deconditioning that occurs when a limb is immobilized,long term hospitalization due to illness or injury, and alcoholism.

An intact androgen receptor (AR) signaling pathway is crucial forappropriate development of skeletal muscles. Furthermore, an intactAR-signaling pathway increases lean muscle mass, muscle strength andmuscle protein synthesis.

Muscle wasting, if left unabated, can have dire health consequences. Forexample, the changes that occur during muscle wasting can lead to aweakened physical state that is detrimental to an individual's health,resulting in increased susceptibility to infraction and poor performancestatus. In addition, muscle wasting is a strong predictor of morbidityand mortality in patients suffering from cachexia and AIDS.

New innovative approaches are urgently needed at both the basic scienceand clinical levels to develop compounds which are useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with Androgen Decline in Aging Male(ADAM), such as fatigue, depression, decreased libido, sexualdysfunction, erectile dysfunction, hypogonadism, osteoporosis, hairloss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benignprostate hyperplasia, alterations in mood and cognition and prostatecancer; c) treatment of conditions associated with ADIF, such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of chronic muscularwasting; e) decreasing the incidence of, halting or causing a regressionof prostate cancer; f) oral androgen replacement and/or other clinicaltherapeutic and/or diagnostic areas.

A wide variety of diseases and/or conditions are affected byhypogonadism, and catabolic effects, including kidney disease, centralnervous system injuries, burns and chronic wounds.

In the United States (US), there is a rising incidence and prevalence ofkidney failure. The number of patients enrolled in end-stage renaldisease (ESRD) Medicare-funded programs has increased from approximately10,000 beneficiaries in 1973 to 86,354 in 1983, and to 431,284 as ofDec. 31, 2002. In 2002 alone, 100,359 patients entered the US ESRDprogram. Chronic kidney disease (CKD) is a precursor to ESRD and occurswhen the kidneys are not able to adequately remove wastes from the body.CKD is a slowly progressing disease, in which diabetes, hypertension andanemia may be co-morbid conditions.

CKD is diagnosed using a staging system that demonstrates the amount ofkidney function available (stage 1=normal kidney function) and patientsoften do not present symptoms in the early stages. Stage 5 of CKD isESRD, which is a complete or near complete failure of the kidneys andusually occurs when kidney function is less than 10% of baseline.

Accompanying symptoms associated with ESRD include hypogonadism,involuntary weight loss, fatigue and others.

Burns result in a testosterone reduction, nitrogen level reduction and areduction in bone mineral density (BMD), which may persist even as longone year following the injury and is associated with impaired woundhealing, increased infection risks, erosion of lean body mass, hamperedrehabilitation, and delayed reintegration of burn survivors intosociety. Catabolic effects initiated as a result of the burn lead tosignificant involuntary weight loss, further compounding the problem.

Spinal cord injuries may result in the alteration centralneurotransmitter secretion or production, which in turn may cause ahypothalamus-pituitary-adrenal axis dysfunction, leading to decreases intestosterone and other hormone levels. SCI or other acute illness ortrauma characteristically includes heightened catabolism in conjunctionwith the lowered anabolic activity resulting in a condition that isprone to loss of lean body tissue. As long as the catabolic process goesuninterrupted, disturbed nutrient utilization will continue. The effectsof the loss of lean body mass include the development of wounds andimpaired healing mechanisms. Because of poor nutrition and proteincombined with immobilization, patients with spinal cord injury are athigh risk for bed sores.

Chronic wounds may be caused by any number of conditions, includingdiabetes, circulatory problems, immobilization and others. Compoundingthe problem, for example in diabetes, is the presence of neuropathy,which increases the risk of foot ulceration.

While there are many treatments and therapies for these conditions, noneare ideal. Since the androgen receptor (AR) signaling pathway has beenshown to increase lean muscle mass, muscle strength and muscle proteinsynthesis, and since hypogonadism accompanies these conditions,molecules targeting the AR signaling pathway may be useful in treatingthese diseases and/or conditions.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides, a compoundrepresented by the structure of formula (I):

wherein Q₂ is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR; andR is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;or its isomer, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate or any combination thereof.

In one embodiment, the present invention provides, a compoundrepresented by the structure of formula II:

-   -   or its isomer, pharmaceutically acceptable salt, pharmaceutical        product, N-oxide, hydrate or any combination thereof.

In one embodiment, the present invention provides, a compoundrepresented by the structure of formula III:

wherein

-   -   X is a bond, O, CH₂, NH, Se, PR, NO or NR;    -   G is O or S;    -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is H, F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃,        NHCOR, alkyl, arylalkyl, OR, NH₂, NHR, N(R)₂, SR;    -   R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR, CF₃, Sn(R)₃,        or    -   R₃ together with the benzene ring to which it is attached forms        a fused ring system represented by the structure:    -   Z is NO₂, CN, Cl, F, Br, I, H, COR, COOH, or CONHR;    -   Y is CF₃, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, formyl, H,        F, Br, Cl, I, CN, or Sn(R)₃;    -   Q is H, alkyl, halogen, CF₃, CN CR₃, Sn(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R,        SR; or Q together with the benzene ring to which it is attached        is a fused ring system represented by structure A, B or C:    -   n is an integer of 1-4; and    -   m is an integer of 1-3;    -   or its isomer, pharmaceutically acceptable salt, pharmaceutical        product, N-oxide, hydrate or any combination thereof.

In one embodiment, Z, Y and Q are not H. In one embodiment, Z, Y, Q andR₂ are not H, if R₃ is H. In one embodiment, Z, Y, Q and R₃ are not H,if R₂ is H.

In one embodiment, Z is NO₂, CN, Cl, F, Br, I, COR, COOH, or CONHR; Y isCF₃, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, formyl, F, Br, Cl, I,CN, or Sn(R)₃; and R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR,CF₃, Sn(R)₃. According to this aspect, and in one embodiment, neither R₂nor Q is H.

In one embodiment, the present invention provides a compoundcharacterized by the structure of formula IV:

In one embodiment, the present invention provides a compositioncomprising the compound of formula (I), (II), (III) or (IV) and/or itsderivative, isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, hydrate, N-oxide or any combination thereof.

In one embodiment, the compounds of this invention are selectiveandrogen receptor modulators.

In one embodiment, the compositions of this invention further comprise atherapeutic agent, which in one embodiment is an anti-cancer agent, animmunomodulating agent, an agent treating diabetes, an agent treatingthe nervous system, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating adermatological disease, or condition, an anti-infective agent, an agenttreating the liver, an agent treating the kidney, an agent treating ametabolic disease, an agent treating a wasting disease, a gene therapyagent, an agent treating the endocrine system, a vitamin, astomatognathic agent, a urogenital agent, behavior-modulating agent, anagent treating the respiratory system, an agent treating the hemicsystem, an agent treating an ophthalmic disease, or any combinationthereof.

In one embodiment, the therapeutic agent is an anti-androgen, anantiestrogen, a monoclonal antibody, a chemotherapeutic agent, animmunosuppressive or anti-inflammatory agent, an immunostimulatoryagent, a sulfonylurea, meglitnide, insulin, biguanide,thiazolidinedione, or alpha-glucosidase inhibitor, an adrenomimeticagent, adrenoceptor antagonist, cholinomimetic agent, a muscarinicblocker, a ganglionic blocker, an anesthetic agent, an analgesic agent,an agent treating neuromuscular transmission, a nervous systemstimulant, a sedative agent, neurodegenerative disorder medication,antiepileptic agent, antipsychotic agent, anti-addiction agent, ananti-arrhythmic agent, an anti-anginal agent, a vasocative agent, acalcium channel blocker, an antihypertensive agent, a diuretic agent, ananticoagulant or fibrinolytic agent, a hypocholesterolemic agent, anopioid, 5-HT3 receptor antagonist, adsorbent agent, bulking agent, astool softening or laxative agent, cathartic agent, an antiemetic agent,an emetic agent, an antacid agent, an H2-receptor antagonist, a protonpump inhibitor, a 5-aminosalicylate agent, a prostaglandin, aglucocorticosteroid, a retinoid, photochemotherapeutic agent, aphotodynamic agent, aminolevulinic acid, dapsone, pyrethrin, pyrethroid,thalidomide, an antimalarial agent, an antimicrobial agent, anantifungal agent, an antiviral agent, a sulfonamide, a trimethoprimagent, a quinolone agent, an oxazolidinone agent, an antiseptic agent, abeta-lactam agent, an aminoglycoside agent, a tetracycline agent, achloramphenicol agent, a macrolide agent, a lincosamide agent, abacitracin agent, a glycopeptide agent, a polymyxin agent, anantiprotozoal agent, an antithelmintic agent, a cortisone, a colchicine,a methotrexate, a ursodeoxycholic acid, a penicillamine, a vitamin,glucosidase alpha, sodium bicarbonate, bisphosphonate, biotin,allopurinol, levodopa, diazepam, phenobarbital, haloperidol, folic acid,haptoglobin, carnitine, a steroid, cannabinoid metoclopramid, cisapride,medroxyprogesterone acetate, megestrol acetate, cyproheptadine,hydrazine sulfate, pentoxifylline, thalidomide, anticytokine antibodies,cytokine inhibitors, eicosapentaenoic acid, indomethacin, ibuprofen,melatonin, insulin, growth hormone, clenbuterol, pancreas extract,cabergoline, bromocriptine, thyroxine, gonadotropin, glucocorticoid,glucocorticoid analogue, corticotrophin, metyrapone, aminoglutethimide,mitotane, ketoconazole, mifepristone, dexamethasone somatostatinanalogue, gonadotropin-releasing hormone analogue, leuprolide,goserelin, antidiuretic hormone, antidiuretic hormone analogue,oxytocin, estrogen, progestin, specific estrogen receptor modulator(SERM), uterine, stimulant, uterine relaxant, androgen, antiandrogen,prostaglandin, dopamine receptor agonist, alpha-adrenoreceptor blocker,anabolic steroid, an antianxiety agent, an antipsychotic agent, anantidepressant, beta-2 agonist, anticholinergic bronchodilator,theophylline, aminophylline, nedocromil sodium, sodium cromoglycate,leukotriene receptor antagonist, corticosteroid, expectorant, mucolyticagent, antihistamine, pseudoephedrine, or a neuraminidase inhibitor,betagan, betimol, timoptic, betoptic, betoptic, ocupress, optipranolol,xalatan, alphagan, azopt, trusopt, cospot, pilocar, pilagan, propine,opticrom, acular, livostin, alomide, emadine, patanol, alrex, dexacidin,maxitrol, tobradex, blephamide, ocufen, voltaren, profenal, pred forte,econpred plus, eflone, flarex, inflamase forte, inflamase mild, lotemax,vexol, polytrim, illotycin, ciloxan, ocuflox, tobrex, or garamycin, orany combination thereof.

In one embodiment, this invention provides a method of binding aselective androgen receptor modulator compound to an androgen receptor,comprising the step of contacting the androgen receptor with thecompound of this invention or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, hydrate, N-oxide orany combination thereof, or a composition comprising the same, in anamount effective to bind the selective androgen receptor modulatorcompound to the androgen receptor.

In one embodiment, this invention provides a method of suppressingspermatogenesis in a subject comprising contacting an androgen receptorof the subject with the compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,hydrate, N-oxide or any combination thereof, or a composition comprisingthe same, in an amount effective to suppress sperm production.

In one embodiment, this invention provides a method of contraception ina male subject, comprising the step of administering to the subject acompound of this invention or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, hydrate, N-oxide or anycombination thereof, or a composition comprising the same, in an amounteffective to suppress sperm production in the subject, thereby effectingcontraception in the subject.

In one embodiment, this invention provides a method of hormone therapycomprising the step of contacting an androgen receptor of a subject acompound of this invention or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, hydrate, N-oxide or anycombination thereof, or a composition comprising the same, in an amounteffective to effect a change in an androgen-dependent condition.

In one embodiment, this invention provides a method of treating asubject suffering from prostate cancer, comprising the step ofadministering to said subject a compound of this invention, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, hydrate, N-oxide or any combination thereof, or a compositioncomprising the same in an amount effective to treat prostate cancer inthe subject.

In one embodiment, this invention provides a method of delaying theprogression of prostate cancer in a subject suffering from prostatecancer, comprising the step of administering to said subject a compoundof this invention or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate, or any combinationthereof, or a composition comprising the same in an amount effective todelay the progression of prostate cancer in the subject.

In one embodiment, this invention provides a method of treating abone-related disorder in a subject, or increasing a bone mass in asubject, promoting bone formation in a subject, administering aneffective amount of a compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,hydrate, N-oxide or any combination thereof, or a composition comprisingthe same, in an amount effective to treat said bone-related disorder.

According to this aspect, and in one embodiment, the subject suffersfrom osteoporosis, osteopenia, increased bone resorption, bone fracture,bone frailty, loss of bone mineral density (BMD), or any combinationthereof. In one embodiment, the method increases the strength of a boneof said subject. In one embodiment, the compound stimulates or enhancesosteoblastogenesis, or in another embodiment the compound inhibitsosteoclast proliferation.

In one embodiment, this invention provides a method of treating,reducing the incidence of, delaying progression of, reducing theseverity of, or alleviating symptoms associated with a muscle wastingdisorder in a subject, comprising the step of administering to said acompound of this invention or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, hydrate, N-oxide or anycombination thereof, or a composition comprising the same, in an amounteffective to treat the muscle wasting disorder in said subject.

According to this aspect, and in one embodiment, the muscle wastingdisorder is due to a pathology, illness, disease or condition. In oneembodiment, the pathology, illness, disease or condition isneurological, infectious, chronic or genetic. In one embodiment, thepathology, illness, disease or condition is a Muscular Dystrophy, aMuscular Atrophy, X-linked spinal-bulbar Muscular Atrophy (SBMA), aCachexia, malnutrition, Leprosy, Diabetes, Renal Disease, ChronicObstructive Pulmonary Disease (COPD), Cancer, end stage Renal failure,Sarcopenia, Emphysema, Osteomalacia, HIV Infection, AIDS, orCardiomyopathy.

In one embodiment, the muscle wasting disorder is an age-associatedmuscle wasting disorder; a disuse deconditioning-associated musclewasting disorder; or the muscle wasting disorder is due to chronic lowerback pain; burns; central nervous system (CNS) injury or damage;peripheral nerve injury or damage; spinal cord injury or damage;chemical injury or damage; or alcoholism.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of diabetes in a human subject, comprisingadministering an effective amount of a compound of this invention or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof, to said subject.

In one embodiment, this invention provides, a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of glucose intolerance in a human subject,comprising the step of administering an effective amount of a compoundof this invention or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of hyperinsulinemia in a human subject,comprising the step of administering an effective amount of a compoundof this invention or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of insulin resistance in a human subject,comprising the step of administering an effective amount of a compoundof this invention or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of diseases associated with diabetescomprising the step of administering an effective amount of a compoundof this invention or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of fatty liver conditions in a humansubject, comprising the step of administering an effective amount of acompound of this invention or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, N-oxide, hydrate or anycombination thereof to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing the pathogenesis of cardiovascular disease in a humansubject, comprising the step of administering an effective amount of acompound of this invention or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, N-oxide, hydrate or anycombination thereof to said subject.

In one embodiment, this invention provides a method of treating reducingthe severity of, reducing the incidence of, delaying the onset of, orreducing the pathogenesis of cachexia in a subject, comprising the stepof administering an effective amount of a compound of this invention orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof to said subject.

In one embodiment, this invention provides a method of treating adisease or condition of the eye of a subject, comprising the step ofadministering an effective amount of a compound of this invention or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof to the subject. Inone embodiment, the disease or condition of the eye comprises Sjogren'ssyndrome, or xerophthalmia.

In one embodiment, the present invention provides a method of reducing afat mass in a subject comprising the step of administering an effectiveamount of a compound of this invention or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof to the subject.

In one embodiment, the present invention provides a method of increasinga lean mass in a subject comprising the step of administering aneffective amount of a compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof to the subject.

In another embodiment, this invention provides a method of suppressingspermatogenesis; contraception in a male; hormone therapy; treatingprostate cancer; delaying the progression of prostate cancer; treating abone-related disorder in a subject, or increasing a bone mass in asubject and/or promoting bone formation in a subject; treating, reducingthe incidence of, delaying progression of, reducing the severity of, oralleviating symptoms associated with a muscle wasting disorder;treating, reducing the severity of, reducing the incidence of, delayingthe onset of, or reducing pathogenesis of diabetes; treating, reducingthe severity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of glucose intolerance; treating, reducing theseverity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of hyperinsulinemia; treating, reducing theseverity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of insulin resistance; treating, reducing theseverity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of diseases associated with diabetes; treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of fatty liver conditions; treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of cardiovascular disease; treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of cachexia; treating a disease orcondition of the eye; reducing a fat mass; or increasing a lean mass ina subject, comprising the step of administering an effective amount of acompound of this invention or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, N-oxide, hydrate or anycombination thereof to the subject as herein described.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be understood and appreciated more fully fromthe following detailed description taken in conjunction with theappended drawings in which:

FIG. 1: Synthetic schemes for the preparation of compound of formula II.FIG. 1A is a synthetic scheme for the preparation of an (S) enantiomerof a compound of formula II (S-II). FIG. 1B is a synthetic scheme forthe preparation of an (R) enantiomer of a compound of formula II (R-II).FIG. 1C is a synthetic scheme for the preparation of an (S) enantiomerof a compound of formula II (S-II) including an oxirane intermediate.FIG. 1D is a synthetic scheme for the preparation of an (R) enantiomerof a compound of formula II (R-II) including an oxirane intermediate.FIG. 1E is a synthetic scheme for the preparation of an (S) enantiomerof a compound of formula II (S-II) involving B-ring addition prior toA-ring addition. FIG. 1F is a synthetic scheme for the preparation of an(R) enantiomer of a compound of formula II (R-II) involving B-ringaddition prior to A-ring addition. FIG. 1G is a synthetic scheme for thepreparation of an (S) enantiomer of a compound of formula II (S-II)using 2-tribromomethyl-[1,3]dioxolan-4-one intermediate and involvingB-ring addition prior to A-ring addition. FIG. 1H is a synthetic schemefor the preparation of an (R) enantiomer of a compound of formula II(R-II) using 2-tribromomethyl-[1,3]dioxolan-4-one intermediate andinvolving B-ring addition prior to A-ring addition. FIG. 1I is asynthetic scheme for preparation of a racemic mixture of a compound offormula II, involving oxazolidinedione intermediate and B ring additionprior to A ring. FIG. 1J is a synthetic scheme for preparation of aracemic mixture of a compound of formula II, involving an oxiraneintermediate and A ring addition prior to B ring. FIG. 1K is a syntheticscheme for preparation of a large scale of an (S) enantiomer of acompound of formula II (S-II). FIG. 1L is a synthetic scheme forpreparation of a large scale of an (S) enantiomer of a compound offormula II (S-II), including an oxirane intermediate.

FIG. 2: Anabolic and androgenic pharmacology of Compound II.

FIG. 3: Levator ani weight in castrated rats.

FIG. 4: Prostate weight in castrated rats.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the following detailed description, numerous specific details are setforth in order to provide a thorough understanding of the invention.However, it will be understood by those skilled in the art that thepresent invention may be practiced without these specific details. Inother instances, well-known methods, procedures, and components have notbeen described in detail so as not to obscure the present invention.

This invention provides, in one embodiment, a substituted acylanilidecharacterized by the structure of Formula I. In one embodiment, thecompound is a SARM. IN one embodiment, the compound is useful intreating a variety of conditions or diseases, including, inter alia,oral testosterone replacement therapy, male contraception, maintainingsexual desire in women, osteoporosis, treating prostate cancer and/orimaging prostate cancer. In some embodiments, the compounds of thisinvention are nonsteroidal ligands for the AR and exhibit androgenicand/or anabolic activity. In some embodiments, the compounds are partialagonists or partial antagonists in a tissue selective manner. In someembodiments, the compounds are full agonists or full antagonists in atissue selective manner, which in some embodiments, allows fortissue-selective androgenic and/or anabolic effects. These agents may beactive alone or in combination with progestins or estrogens, or otheragents, as herein described. In other embodiments, the agents areagonists, antagonists, partial agonists or partial antagonists.

In some embodiments, this invention provides compounds, which are usefulin androgen replacement therapy (ART), useful in a) improving bodycomposition; b) increasing bone mineral density (BMD); c) increasingbone mass; d) increasing bone strength; e) improving bone function; f)decreasing fracture risk; g) increasing muscle strength; h) increasingmuscle function; i) improving exercise tolerance; j) enhancing libido;k) improving sexual performance; and/or 1) improving mood and/or m)improving cognition.

In some embodiments, this invention provides synthetic processes ofpreparation of the SARM compounds of this invention. In someembodiments, the invention provides compositions comprising theselective androgen modulator compounds or use of the same for binding anAR, modulating spermatogenesis, bone formation and/or resorption,treating muscle wasting or diseases associated with muscle wasting,treating prostate cancer, and/or providing hormonal therapy forandrogen-dependent conditions.

In one embodiment, the present invention provides, a compoundrepresented by the structure of formula (I):

wherein Q₂ is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR; andR is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;or its isomer, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate or any combination thereof.

In one embodiment, the present invention provides, a compoundrepresented by the structure of formula II:

-   -   or its isomer, pharmaceutically acceptable salt, pharmaceutical        product, N-oxide, hydrate or any combination thereof.

In one embodiment, the present invention provides, a compoundrepresented by the structure of formula III:

wherein

-   -   X is a bond, O, CH₂, NH, Se, PR, NO or NR;    -   G is O or S;    -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is H, F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃,        NHCOR, alkyl, arylalkyl, OR, NH₂, NHR, N(R)₂, SR;    -   R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR, CF₃, Sn(R)₃,        or    -   R₃ together with the benzene ring to which it is attached forms        a fused ring system represented by the structure:    -   Z is NO₂, CN, Cl, F, Br, I, H, COR, COOH, or CONHR;    -   Y is CF₃, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, formyl, H,        F, Br, Cl, I, CN, or Sn(R)₃;    -   Q is H, alkyl, halogen, CF₃, CN CR₃, Sn(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R,        SR; or Q together with the benzene ring to which it is attached        is a fused ring system represented by structure A, B or C:    -   n is an integer of 1-4; and    -   m is an integer of 1-3;    -   wherein if R₃ is H, then none of Z or Y or R₂ or Q are H; or an        isomer, pharmaceutically acceptable salt, pharmaceutical        product, N-oxide, hydrate thereof or any combination thereof.

In one embodiment, the present invention provides a compound of formulaII wherein X is O. In another embodiment, the present invention providesa compound of formula II wherein T is OH. In another embodiment, thepresent invention provides a compound of formula II wherein R₁ is CH₃.In another embodiment, the present invention provides a compound offormula II wherein Z is CN. In another embodiment, the present inventionprovides a compound of formula II wherein Z is F. In another embodiment,the present invention provides a compound of formula II wherein Z isNO₂. In another embodiment, the present invention provides a compound offormula II, wherein Y is CH₃. In another embodiment, the presentinvention provides a compound of formula II, wherein Y is H. In anotherembodiment, the present invention provides a compound of formula IIwherein Y is CF₃. In another embodiment, the present invention providesa compound of formula II, wherein Y is Cl. In another embodiment, thepresent invention provides a compound of formula II wherein R₃ is H andnone of Y, Z, Q or R₂ are H. In another embodiment, the presentinvention provides a compound of formula II wherein R₃ is CN. In anotherembodiment, the present invention provides a compound of formula IIwherein R₃ is Cl. In another embodiment, the present invention providesa compound of formula II wherein R₃ is F. In another embodiment, thepresent invention provides a compound of formula II wherein Q is CN. Inanother embodiment, the present invention provides a compound of formulaII wherein Q is F. In another embodiment, the present invention providesa compound of formula II wherein Q is Cl.

In one embodiment, the present invention provides a compoundcharacterized by the structure of formula IV:

wherein R₃, m and n are as described for the structure of formula III.

In one embodiment, the present invention provides a compoundcharacterized by the structure of formula V:

wherein

A and B rings are independently carbocyclic, heterocyclic, aryl,heteroaryl, bicyclic, polycyclic, or spiro rings.

T is OH, OR, —NHCOCH₃, or NHCOR;

X is bond, O, CH₂, NH, S, SO, SO₂, Se, PR, NO or NR;

Z is NO₂, CN, COR, COOH, or CONHR;

Y is CF₃, alkoxy, hydroxyalkyl, alkylaldehyde, formyl, F, Br, Cl, I, CN,alkyl or Sn(R)₃;

Q is H, alkyl, halogen, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃,NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR,NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R, SR;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃; aryl, phenyl, halogen, alkenyl, alkynyl, haloalkenyl,haloalkynyl, perhaloalkyl, or OH;

R₁CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃, NHCOR,alkyl, arylalkyl, allyl, alkenyl, alkynyl, OR, NH₂, NHR, N(R)₂, SR;

R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR, CF₃, alkyl, arylalkyl,allyl, alkenyl, alkynyl, Sn(R)₃;

C, D, E and F are independently a bond, alkyl (C₁-C₅), alkenyl (C₁-C₅),alkynyl (C₁-C₅), alkoxy (C₁-C₅), alkylester (C₁-C₅), alkylether (C₁-C₅),alkylamide (C₁-C₅), alkylcarbamate (C₁-C₅), alkyl amine (C₁-C₅), alkylketone (C₁-C₅), alkyl-COOH(C₁-C₅);

M is substituted or unsubstituted amide, substituted or unsubstitutedthioamide substituted or unsubstituted reverse amide, substituted orunsubstituted reverse thioamide, substituted or unsubstituted amine,substituted or unsubstituted carbamate, substituted or unsubstitutedurea, substituted or unsubstituted thiourea substituted or unsubstitutedester, substituted or unsubstituted reverse ester, or substituted orunsubstituted ether; n is 1-3; and

m is 1-4.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula V:

wherein

A and B rings are independently carbocyclic, heterocyclic, aryl,heteroaryl, bicyclic, polycyclic, or spiro rings.

T is OH, OR, —NHCOCH₃, or NHCOR;

X is bond, O, CH₂, NH, S, SO, SO₂, Se, PR, NO or NR;

Z is NO₂, CN, COR, COOH, or CONHR;

Y is CF₃, alkoxy, hydroxyalkyl, alkylaldehyde, formyl, F, Br, Cl, I, CN,alkyl or Sn(R)₃;

Q is H, alkyl, halogen, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃,NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR,NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R, SR;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃; aryl, phenyl, halogen, alkenyl, alkynyl, haloalkenyl,haloalkynyl, perhaloalkyl, or OH;

R₁CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃, NHCOR,alkyl, arylalkyl, allyl, alkenyl, alkynyl, OR, NH₂, NHR, N(R)₂, SR;

R₃ is hydrogen;

C, D, E and F are independently a bond, alkyl (C₁-C₅), alkenyl (C₁-C₅),alkynyl (C₁-C₅), alkoxy (C₁-C₅), alkylester (C₁-C₅), alkylether (C₁-C₅),alkylamide (C₁-C₅), alkylcarbamate (C₁-C₅), alkyl amine (C₁-C₅), alkylketone (C₁-C₅), alkyl-COOH(C₁-C₅);

M is substituted or unsubstituted amide, substituted or unsubstitutedthioamide substituted or unsubstituted reverse amide, substituted orunsubstituted reverse thioamide, substituted or unsubstituted amine,substituted or unsubstituted carbamate, substituted or unsubstitutedurea, substituted or unsubstituted thiourea substituted or unsubstitutedester, substituted or unsubstituted reverse ester, or substituted orunsubstituted ether;

n is 1-3; and

m is 1-4.

In another embodiment, preferred examples of ring A of formula V includecarbazoles, norharmans, saccharins, isatins, purines, isatoicanhydrides, benzisoxazoles, benzisthiazoles, quinolines, quinolinones,tetrahydroquinolines, isoquinolines, tetrahydroisoquinolines, azulenes,1-aza-azulenes, and 1,3-diaza-azulenes.

In one embodiment, preferred examples of ring B, of formula V, includepyridines, pyrazines, pyrimidines, pyridazines, thiophenes, pyrroles,furans, triazines, tetrazines, isothiazoles, thiazoles, isoxazoles,oxazoles, furazans, imidazoles, pyrazoles, thiadiazoles, triazoles, andtetrazoles.

In another embodiment, less preferred examples of rings A and B includethe following: aromatics such as benzene, thiophenes, pyrroles, furans,isothiazoles, thiazoles, isoxazoles, oxazoles, furazans, imidazoles,pyrazoles, thiadiazoles, 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles,pyridines, pyrazines, pyrimidines, pyridazines, 1,3,5-triazines,tetrazines, bicyclics such as indolines, isoindolines, indenes,pentalenes, isoindoles, indolenines, idolizines, indazoles, oxindoles,isatins, saccharins, quinolizidines, pyrrolizidines,tetrahydroquinolines, tetrahydroisoquinolines, decahydroquinolines,decahydroisoquinolines, heterocyclics and carbocyclics such as1,2,4-oxadiazoles, aziridines, azetidines, pyrrolidines, pyrrolidinones,piperidines, piperidinones, piperazines, 2,5-dioxopiperazines, A2- andA3-thiazolines, oxiranes, oxetans, tetrahydrofurans, tetrahydropyrans,thiirans, thietans, thiolans, tetrahydrothiopyrans, azepines, oxepines,sultones, isoxazolidines, sultams, 5-oxazolones, oxazolidines,succinimides, ethylene, ureas, imidazolines, thioimidazolidines,hydantoins, thiohydantoins, oxazolidinediones, 1,4-dihydropyridines,cyclopentadieneones, cyclopentadienes, 1,3-oxathioles,1,3-oxazinan-2-ones, fulvenes, fulvalenes, pyrans, 1,4-thiazines,4-pyridthiones, 4-pyrones, 2-pyrimidones, uracils, barbituric acids, and3-pyrazolidones.

In one embodiment, the present invention provides a compound representedby the structure of formula VI:

wherein A and B rings, Y, Z, Q, R₂, R₃, C, D, E, T, R₁, X, n, and m areas defined in compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula VI:

wherein R₃ is hydrogen, A and B rings, Y, Z, Q, R₂, C, D, E, T, R₁, X n,and m are as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula 15A:

wherein A and B rings, Y, Z, Q, R₂, R₃, C, D, E, T, R₁, X, n, and m areas defined in compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula 15A:

wherein R₃ is hydrogen, A and B rings, Y, Z, Q, R₂, C, D, E, T, R₁, X n,and m are as defined in compound of formula V.

In another embodiment, preferred examples of ring A of formula VI andVIA include carbazoles, norharmans, saccharins, indoles, isoindoles,indene, benzothiophene, benzofuran, α and β naphthenes,dihydronaphthenes, tetrahydronaphthylenes, azepines, diazepines,isatins, purines, isatoic anhydrides, benzisoxazoles, benzisthiazoles,benzoxazole, benzthiazoles, quinolines, quinolinones,tetrahydroquinolines, isoquinolines, tetrahydroisoquinolines, azulenes,1-aza-azulenes, and 1,3-diaza-azulenes.

In one embodiment, the present invention provides a compound representedby the structure of formula VII:

wherein

A and B rings are independently carbocyclic, heterocyclic, aryl,heteroaryl, bicyclic, polycyclic, or spiro rings.

X is bond, O, CH₂, NH, S, SO, SO₂, Se, PR, NO or NR;

Z is NO₂, CN, COR, COOH, or CONHR;

Y is CF₃, alkoxy, hydroxyalkyl, alkylaldehyde, formyl, F, Br, Cl, I, CN,alkyl or Sn(R)₃;

Q is H, alkyl, halogen, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃,NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR,NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R, SR;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃; aryl, phenyl, halogen, alkenyl, alkynyl, haloalkenyl,haloalkynyl, perhaloalkyl, or OH;

R₁CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;

R₂ is F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃, NHCOR,alkyl, arylalkyl, allyl, alkenyl, alkynyl, OR, NH₂, NHR, N(R)₂, SR;

R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR, CF₃, alkyl, arylalkyl,allyl, alkenyl, alkynyl, Sn(R)₃;

C, D, E and F are independently a bond, alkyl (C₁-C₅), alkenyl (C₁-C₅),alkynyl (C₁-C₅), alkoxy (C₁-C₅), alkylester (C₁-C₅), alkylether (C₁-C₅),alkylamide (C₁-C₅), alkylcarbamate (C₁-C₅), alkyl amine (C₁-C₅), alkylketone (C₁-C₅), alkyl-COOH(C₁-C₅);

n is 1-3; and

m is 1-4; wherein

if C and E are bonds, X is CH₂ or a bond than ring B is not a 5 memberedring comprising one sulfur atom and one nitrogen atom; and

if each of C, D, E and F is a bond, and each of A and B is a phenylring, and R₃ is H, then none of Z, Y, Q or R₂ are H.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula VII:

wherein R₃ is hydrogen, A and B rings, Y, Z, Q, R₂, C, E, X, n, and mare as defined hereinabove.

In another embodiment, the thiazine may include thiazolidine,thiazolidinone, or thiazole.

In one embodiment, the present invention provides a compound representedby the structure of formula VIII:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, T, R₁, X, n and m are asdefined in compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula VIII:

wherein R₃ is hydrogen, A and B rings, Y, Z, Q, R₂, D, T, R₁, X, n and mare as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula IX:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E T, R₁, X, n and m are asdefined in compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula IX:

wherein R₃ is hydrogen, A and B rings, Y, Z, Q, R₂, D, E T, R₁, X, n andm are as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula X:

wherein A and B rings, Y, Z, Q, R₂, R₃, C, D, T, R₁, n and m are asdefined in compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula X:

wherein R₃ is hydrogen, A and B rings, Y, Z, Q, R₂, C, D, T, R₁, n and mare as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XI:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, T, R₁, n and m are asdefined in compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XI:

wherein R₃ is hydrogen and A and B rings, Y, Z, Q, R₂, D, E, T, R₁, nand m are as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XII:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, T, R₁, n and m are asdefined in compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XII:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, T, R₁, n and m are asdefined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XIII:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, T, R₁, n and m are asdefined in compound of formula V; andwherein ring C is benzene, phenyl, benzyl, thiophenes, pyrroles, furans,isothiazoles, thiazoles, isoxazoles, oxazoles, furazans, imidazoles,pyrazoles, thiadiazoles, 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles,pyridines, pyrazines, pyrimidines, pyridazines, 1,3,5-triazines,tetrazines, hydantoin, thiohydantoin, oxazolidinedione,cyclopentadieneone, cyclopentadiene, 1,3-oxathiole, fulvene, thiophene,pyrrole, furan, isoxazole, pyrazole, isothiazole, thiazole, oxazole,imidazole, imidazoline, pyridazine, pyrazine, pyrimidine, pyridine,fulvalene, quinazoline, phthalazine, cinnoline, quinoxaline, quinoline,isoquinoline, quinolinone, isoquinolinone, chroman, chromene, coumarin,isocoumarin.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XIII:

Wherein R₃ is hydrogen, A and B rings, Y, Z, Q, R₂, D, E, T, R₁, n and mare as defined in compound of formula V; andwherein ring C is benzene, phenyl, benzyl, thiophenes, pyrroles, furans,isothiazoles, thiazoles, isoxazoles, oxazoles, furazans, imidazoles,pyrazoles, thiadiazoles, 1,2,3-triazoles, 1,2,4-triazoles, tetrazoles,pyridines, pyrazines, pyrimidines, pyridazines, 1,3,5-triazines,tetrazines, hydantoin, thiohydantoin, oxazolidinedione,cyclopentadieneone, cyclopentadiene, 1,3-oxathiole, fulvene, thiophene,pyrrole, furan, isoxazole, pyrazole, isothiazole, thiazole, oxazole,imidazole, imidazoline, pyridazine, pyrazine, pyrimidine, pyridine,fulvalene, quinazoline, phthalazine, cinnoline, quinoxaline, quinoline,isoquinoline, quinolinone, isoquinolinone, chroman, chromene, coumarin,isocoumarin.

In one embodiment, the present invention provides a compound representedby the structure of formula XIV:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, X, n and m are as definedin compound of formula V; andwherein

is hydantoin, thiohydantoin, oxazolidinedione, cyclopentadieneone,cyclopentadiene, 1,3-oxathiole, fulvene, thiophene, pyrrole, furan,isoxazole, pyrazole, isothiazole, thiazole, oxazole, imidazole,imidazoline, pyridazine, pyrazine, pyrimidine, pyridine, fulvalene,quinazoline, phthalazine, cinnoline, quinoxaline, quinoline,isoquinoline, quinolinone, isoquinolinone, chroman, chromene, coumarin,isocoumarin.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XIV:

wherein R₃ is hydrogen, and A and B rings, Y, Z, Q, R₂, R₃, D, E, X, nand m are as defined in compound of formula V; andwherein

is hydantoin, thiohydantoin, oxazolidinedione, cyclopentadieneone,cyclopentadiene, 1,3-oxathiole, fulvene, thiophene, pyrrole, furan,isoxazole, pyrazole, isothiazole, thiazole, oxazole, imidazole,imidazoline, pyridazine, pyrazine, pyrimidine, pyridine, fulvalene,quinazoline, phthalazine, cinnoline, quinoxaline, quinoline,isoquinoline, quinolinone, isoquinolinone, chroman, chromene, coumarin,isocoumarin.

In one embodiment, the present invention provides a compound representedby the structure of formula XV:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, X, n and m are as definedin compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XV:

wherein R₃ is hydrogen, and A and B rings, Y, Z, Q, R₂, D, E, X, n and mare as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XVI:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, X, n and m are as definedin compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XVI:

wherein R₃ is hydrogen, and A and B rings, Y, Z, Q, R₂, D, E, X, n and mare as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XVII:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, X, n and m are as definedin compound of formula XVII.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XVII:

wherein R₃ is hydrogen and A and B rings, Y, Z, Q, R₂, D, E, X, n and mare as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XVIII:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, X, n and m are as definedin compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XVIII:

wherein R₃ is hydrogen and A and B rings, Y, Z, Q, R₂, D, E, X, n and mare as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XIX:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, X, n and m are as definedin compound of formula V.

In another embodiment, the present invention provides a selectiveandrogen receptor modulator (SARM) compound represented by the structureof formula XIX:

wherein R₃ is hydrogen and A and B rings, Y, Z, Q, R₂, D, E, X, n and mare as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XX:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, X, n and m are as definedin compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XX:

wherein R₃ is hydrogen and A and B rings, Y, Z, Q, R₂, D, E, X, n and mare as defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XXI:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, X, n and m are as definedin compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XXI:

wherein R₃ is hydrogen, A and B rings, Y, Z, Q, R₂, D, E, X, n and m areas defined in compound of formula V.

In one embodiment, the present invention provides a compound representedby the structure of formula XXII:

wherein A and B rings, Y, Z, Q, R₂, R₃, D, E, X, n and m are as definedin compound of formula V.

In another embodiment, the present invention provides a compoundrepresented by the structure of formula XXII:

wherein R₃ is hydrogen and A and B rings, Y, Z, Q, R₂, D, E, X, n, and mare as defined in compound of formula V.

In other specific non-limiting embodiments, ring A and its substituentsinclude the following schematic structures:

wherein

R₃ and R₄ are independently H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR,CF₃, alkyl, arylalkyl, allyl, alkenyl, alkynyl, Sn(R)₃;

n and q are independently 1-3; and

R, Z and Y are as defined for structure V.

In other non-limiting embodiments, ring B and its substituents includethe following schematic structures:

wherein

R₂ and R₅ are independently H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR,CF₃, alkyl, arylalkyl, allyl, alkenyl, alkynyl, Sn(R)₃;

m and p are independently 1-3; and

R and Q are as defined for structure V.

In other non-limiting embodiments amide M include the followingschematic structures:

wherein each NH or NH₂ groups can be optionally substituted with an Rgroup, and oxygen atoms may be also replaced with sulfur atoms; whereinR is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃; aryl, phenyl, halogen, alkenyl, alkynyl, haloalkenyl,haloalkynyl, alkoxy, perhaloalkyl, or OH.

In one embodiment, the present invention provides a compound of any offormulas I-XXII wherein R₂ is F. In another embodiment, the presentinvention provides a compound of any of formulas I-XXII wherein R₂ isCl. In another embodiment, the present invention provides a compound ofany of formulas I-XXII wherein R₂ is Br. In another embodiment, thepresent invention provides a compound of any of formulas I-XXII whereinR₂ is I. In another embodiment, the present invention provides acompound of any of formulas I-XXII wherein R₂ is CH₃. In anotherembodiment, the present invention provides a compound of any of formulasI-XXII wherein R₂ is OH. In another embodiment, the present inventionprovides a compound of any of formulas I-XXII wherein R₂ is CF₃. Inanother embodiment, the present invention provides a compound of any offormulas I-XXII wherein R₂ is CN. In another embodiment, the presentinvention provides a compound of any of formulas I-XXII wherein R₂ isNO₂. In another embodiment, the present invention provides a compound ofany of formulas I-XXII wherein R₂ is NHCOCH₃. In another embodiment, thepresent invention provides a compound of any of formulas I-XXII whereinR₂ is NHCOCF₃. In another embodiment, the present invention provides acompound of any of formulas I-XXII wherein R₂ is NHCOR In anotherembodiment, the present invention provides a compound of any of formulasI-XXII wherein R₂ is alkyl. In another embodiment, the present inventionprovides a compound of any of formulas I-XXII wherein R₂ is arylalkyl.In another embodiment, the present invention provides a compound of anyof formulas I-XXII wherein R₂ is alkenyl. In another embodiment, thepresent invention provides a compound of any of formulas I-XXII whereinR₂ is alkynyl. In another embodiment, the present invention provides acompound of any of formulas I-XXII wherein R₂ is OR. In anotherembodiment, the present invention provides a compound of any of formulasI-XXII wherein R₂ is NH₂. In another embodiment, the present inventionprovides a compound of any of formulas I-XXII wherein R₂ is NHR. Inanother embodiment, the present invention provides a compound of any offormulas I-XXII wherein R₂ is N(R)₂. In another embodiment, the presentinvention provides a compound of any of formulas I-XXII wherein R₂ isSR.

In one embodiment, the present invention provides a compound of any offormulas I-XXII wherein R₃ is F. In another embodiment, the presentinvention provides a compound of any of formulas I-XXII wherein R₃ isCl. In another embodiment, the present invention provides a compound ofany of formulas I-XXII wherein R₃ is Br. In another embodiment, thepresent invention provides a compound of any of formulas I-XXII whereinR₃ is I. In another embodiment, the present invention provides acompound of any of formulas I-XXII wherein R₃ is CN. In anotherembodiment, the present invention provides a compound of any of formulasI-XXII wherein R₃ is NO₂. In another embodiment, the present inventionprovides a compound of any of formulas I-XXII wherein R₃ is H. Inanother embodiment, the present invention provides a compound of any offormulas I-XXII wherein R₃ is COR. In another embodiment, the presentinvention provides a compound of any of formulas I-XXII wherein R₃ isCOOH. In another embodiment, the present invention provides a compoundof any of formulas I-XXII wherein R₃ is CONHR. In another embodiment,the present invention provides a compound of any of formulas I-XXII R₃is CF₃. In another embodiment, the present invention provides a compoundof any of formulas I-XXII wherein R₃ is Sn(R)₃. In another embodiment,the present invention provides a compound of any of formulas I-XXIIwherein R₃ together with the benzene ring to which it is attached formsa compound represented by the structure:

In one embodiment, the present invention provides a compound of any offormulas I-XXII wherein m is 1. In another embodiment, the presentinvention provides a compound of any of formulas I-XXII wherein m is 2.In another embodiment, the present invention provides a compound of anyof formulas I-XXII wherein m is 3. In another embodiment, the presentinvention provides a compound of any of formulas I-XXII wherein n is 1.In another embodiment, the present invention provides a compound of anyof formulas I-XXII wherein n is 2. In another embodiment, the presentinvention provides a compound of any of formulas I-XXII wherein n is 3.In another embodiment, the present invention provides a compound of anyof formulas I-XXII wherein n is 4.

In one embodiment, this invention provides an analog of the compound offormula I-XXII. In another embodiment, this invention provides aderivative of the compound of formula I-XXII. In another embodiment,this invention provides a prodrug of the compound of formula I-XXII. Inanother embodiment, this invention provides a metabolite of the compoundof formula I-XXII. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of formula I-XXII. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of formula I-XXII. In another embodiment, this inventionprovides a hydrate of the compound of formula I-XXII. In anotherembodiment, this invention provides an N-oxide of the compound offormula I-XXII. In another embodiment, this invention provides apolymorph of the compound of formula I-XXII. In another embodiment, thisinvention provides a crystal of the compound of formula I-XXII. Inanother embodiment, this invention provides an impurity of the compoundof formula I-XXII. In another embodiment, this invention provides acombination of any of an analog, derivative, metabolite, isomer,prodrug, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, hydrate, N-oxide of the compound offormula I-XXII.

As contemplated herein, the present invention relates to the use of aSARM compound and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, polymorph, crystal, impurity or combinations thereof. In oneembodiment, the invention relates to the use of an analog of the SARMcompound. In another embodiment, the invention relates to the use of aderivative of the SARM compound. In another embodiment, the inventionrelates to the use of an isomer of the SARM compound. In anotherembodiment, the invention relates to the use of a metabolite of the SARMcompound. In another embodiment, the invention relates to the use of apharmaceutically acceptable salt of the SARM compound. In anotherembodiment, the invention relates to the use of a pharmaceutical productof the SARM compound. In another embodiment, the invention relates tothe use of a hydrate of the SARM compound. In another embodiment, theinvention relates to the use of an N-oxide of the SARM compound. Inanother embodiment, the invention relates to the use of a polymorph ofthe SARM compound. In another embodiment, the invention relates to theuse of a crystal of the SARM compound. In another embodiment, theinvention relates to the use of an impurity of the SARM compound.

As defined herein, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like. In one embodiment, theterm “isomer” is meant to encompass optical isomers of the SARMcompound. It will be appreciated by those skilled in the art that theSARMs of the present invention contain at least one chiral center.Accordingly, the SARMs used in the methods of the present invention mayexist in, and be isolated in, optically-active or racemic forms. Somecompounds may also exhibit polymorphism. It is to be understood that thepresent invention encompasses any racemic, optically-active,polymorphic, or stereroisomeric form, or mixtures thereof, which formpossesses properties useful in the treatment of androgen-relatedconditions described herein. In one embodiment, the SARMs are the pure(R)-isomers. In another embodiment, the SARMs are the pure (S)-isomers.In another embodiment, the SARMs are a mixture of the (R) and the (S)isomers. In another embodiment, the SARMs are a racemic mixturecomprising an equal amount of the (R) and the (S) isomers. It is wellknown in the art how to prepare optically-active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase).

In one embodiment, this invention encompasses the use of various opticalisomers of the SARM compound. It will be appreciated by those skilled inthe art that the SARMs of the present invention contain at least onechiral center. Accordingly, the SARMs used in the methods of the presentinvention may exist in, and be isolated in, optically-active or racemicforms. Some compounds may also exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, polymorphic, or stereroisomeric form, or mixturesthereof, which form possesses properties useful in the treatment ofandrogen-related conditions described herein. In one embodiment, theSARMs are the pure (R)-isomers. In another embodiment, the SARMs are thepure (S)-isomers. In another embodiment, the SARMs are a mixture of the(R) and the (S) isomers. In another embodiment, the SARMs are a racemicmixture comprising an equal amount of the (R) and the (S) isomers. It iswell known in the art how to prepare optically-active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

The invention includes “pharmaceutically acceptable salts” of thecompounds of this invention, which may be produced, by reaction of acompound of this invention with an acid or base.

Suitable pharmaceutically-acceptable salts of amines of Formula I-V maybe prepared from an inorganic acid or from an organic acid. In oneembodiment, examples of inorganic salts of amines are bisulfates,borates, bromides, chlorides, hemisulfates, hydrobromates,hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates),iodates, iodides, isothionates, nitrate, persulfates, phosphate,sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates,arylsulfonates, halogen substituted alkylsulfonates, halogen substitutedarylsulfonates), sulfonates and thiocyanates.

In one embodiment, examples of organic salts of amines may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilate,algenate, alkane carboxylates, substituted alkane carboxylates,alginates, benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, carboxilate, citrates, camphorates,camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates,calcium edetates, camsylates, carbonates, clavulanates, cinnamates,dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides,decanoates, enanthuates, ethanesulfonates, edetates, edisylates,estolates, esylates, fumarates, formates, fluorides, galacturonategluconates, glutamates, glycolates, glucorate, glucoheptanoates,glycerophosphates, gluceptates, glycollylarsanilates, glutarates,glutamate, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlicacids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoate,hydrofluorate, lactates, lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates, mitrates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates,N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, phenylacetate, pectinates, phenylpropionates, palmitates,pantothenates, polygalacturates, pyruvates, quinates, salicylates,succinates, stearates, sulfanilate, subacetates, tartarates,theophyllineacetates, p-toluenesulfonates (tosylates),trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates,triethiodide, tricarboxylates, undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orphenols may be selected from ammonium, alkali metals to include lithium,sodium, potassium, cesium; alkaline earch metals to include calcium,magnesium, aluminium; zinc, barium, cholines, quaternary ammoniums.

In another embodiment, examples of organic salts of carboxylic acids orphenols may be selected from arginine, organic amines to includealiphatic organic amines, alicyclic organic amines, aromatic organicamines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N′-dibenzylethylenediamines, nicotinamides, organic amines,ornithines, pyridines, picolies, piperazines, procain,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

In one embodiment, the invention also includes N-oxides of the aminosubstituents of the compounds described herein. Also, esters of thephenolic compounds can be made with aliphatic and aromatic carboxylicacids, for example, acetic acid and benzoic acid esters.

This invention provides derivatives of the SARM compounds. In oneembodiment, “derivatives” includes but is not limited to etherderivatives, acid derivatives, amide derivatives, ester derivatives andthe like. In another embodiment, this invention further includeshydrates of the SARM compounds.

In one embodiment, “hydrate” includes but is not limited to hemihydrate,monohydrate, dihydrate, trihydrate and the like.

This invention provides, in other embodiments, metabolites of the SARMcompounds. In one embodiment, “metabolite” means any substance producedfrom another substance by metabolism or a metabolic process.

This invention provides, in other embodiments, pharmaceutical productsof the SARM compounds. The term “pharmaceutical product” refers, inother embodiments, to a composition suitable for pharmaceutical use(pharmaceutical composition), for example, as described herein.

An “alkyl” group refers, in one embodiment, to a saturated aliphatichydrocarbon, including straight-chain, branched-chain and cyclic alkylgroups. In one embodiment, the alkyl group has 1-12 carbons. In anotherembodiment, the alkyl group has 1-7 carbons. In another embodiment, thealkyl group has 1-6 carbons. In another embodiment, the alkyl group has1-4 carbons. The alkyl group may be unsubstituted or substituted by oneor more groups selected from halogen, hydroxy, alkoxy carbonyl, amido,alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino,carboxyl, thio and thioalkyl. In one embodiment, the alkyl group is CH₃.

An “alkenyl” group refers, in another embodiment, to an unsaturatedhydrocarbon, including straight chain, branched chain and cyclic groupshaving one or more double bond. The alkenyl group may have one doublebond, two double bonds, three double bonds etc. Examples of alkenylgroups are ethenyl, propenyl, butenyl, cyclohexenyl etc. In oneembodiment, the alkylene group has 1-12 carbons. In another embodiment,the alkylene group has 1-7 carbons. In another embodiment, the alkylenegroup has 1-6 carbons. In another embodiment, the alkylene group has 1-4carbons. The alkenyl group may be unsubstituted or substituted by one ormore groups selected from halogen, hydroxy, alkoxy carbonyl, amido,alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino,carboxyl, thio and thioalkyl.

A “haloalkyl” group refers to an alkyl group as defined above, which issubstituted by one or more halogen atoms, in one embodiment by F, inanother embodiment by Cl, in another embodiment by Br, in anotherembodiment by I.

An “aryl” group refers to an aromatic group having at least onecarbocyclic aromatic group or heterocyclic aromatic group, which may beunsubstituted or substituted by one or more groups selected fromhalogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio orthioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl,pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl,furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. Inone embodiment, the aryl group is a 4-8 membered ring. In anotherembodiment, the aryl group is a 4-12 membered ring(s). In anotherembodiment, the aryl group is a 6 membered ring. In another embodiment,the aryl group is a 5 membered ring. In another embodiment, the arylgroup is 2-4 fused ring system.

A “hydroxyl” group refers to an OH group. It is understood by a personskilled in the art that when T is OR, R is not OH.

In one embodiment, the term “halogen refers to in one embodiment to F,in another embodiment to Cl, in another embodiment to Br, in anotherembodiment to I.

An “arylalkyl” group refers, in another embodiment, to an alkyl bound toan aryl, wherein alkyl and aryl are as defined above. An example of anarylalkyl group is a benzyl group.

In one embodiment, the term “amide” refers to carbonyl group attached toan amine group. In another embodiment the amide group has the followingschematic structure:

In another embodiment, the amide group is unsubstituted or substitutedvia the nitrogen atom by alkyl (C₁-C₈), aryl (C₁-C₈) group, phenyl,carbocyclic (C₁-C₈) group, heterocyclic(C₁-C₈) group, acyl, alkyl(C₁-C₈) halide, alkenyl (C₁-C₈) group.

In one embodiment, the term “thioamide” refers to C═S group attached toan amine group. In another embodiment the thioamide group has thefollowing schematic structure:

In another embodiment, the thioamide group is unsubstituted orsubstituted via the nitrogen atom by alkyl (C₁-C₈), aryl (C₁-C₈) group,phenyl, carbocyclic (C₁-C₈) group, heterocyclic(C₁-C₈) group, acyl,alkyl (C₁-C₈) halide, alkenyl (C₁-C₈) group.

In one embodiment, the term “reverse amide” refers to amine groupattached to a carbonyl group. In another embodiment the reverse amidegroup has the following schematic structure:

In another embodiment, the reverse amide group is unsubstituted orsubstituted via the nitrogen atom by alkyl (C₁-C₈), aryl (C₁-C₈) group,phenyl, carbocyclic (C₁-C₈) group, heterocyclic(C₁-C₈) group, acyl,alkyl (C₁-C₈) halide, alkenyl (C₁-C₈) group.

In one embodiment, the term “reverse thioamide” refers to amine groupattached to a C═S group. In another embodiment the reverse thioamidegroup has the following schematic structure:

In another embodiment, the reverse thioamide group is unsubstituted orsubstituted via the nitrogen atom by alkyl (C₁-C₈), aryl (C₁-C₈) group,phenyl, carbocyclic (C₁-C₈) group, heterocyclic(C₁-C₈) group, acyl,alkyl (C₁-C₈) halide, alkenyl (C₁-C₈) group.

In one embodiment, the term “carbamate” refers to an ester of a carbamicacid (NH₂COOH). In another embodiment the carbamate group has thefollowing schematic structure:

In another embodiment, the carbamate group is unsubstituted orsubstituted via the nitrogen atom by alkyl (C₁-C₈), aryl (C₁-C₈) group,phenyl, carbocyclic (C₁-C₈) group, heterocyclic(C₁-C₈) group, acyl,alkyl (C₁-C₈) halide, alkenyl (C₁-C₈) group.

In one embodiment, the term “urea” refers to carbonyl-diamide group. Inanother embodiment the urea group has the following schematic structure:

In another embodiment, the urea group is unsubstituted or substituted,independently via each or both of the nitrogen atoms by alkyl (C₁-C₈),aryl (C₁-C₈) group, phenyl, carbocyclic (C₁-C₈) group,heterocyclic(C₁-C₈) group, acyl, alkyl (C₁-C₈) halide, alkenyl (C₁-C₈)group.

In one embodiment, the term “thiourea” refers to an C═S-diamide group.In another embodiment the urea group has the following schematicstructure:

In another embodiment, the thiourea group is unsubstituted orsubstituted, independently via each or both of the nitrogen atoms byalkyl (C₁-C₈), aryl (C₁-C₈) group, phenyl, carbocyclic (C₁-C₈) group,heterocyclic(C₁-C₈) group, acyl, alkyl (C₁-C₈) halide, alkenyl (C₁-C₈)group.

In one embodiment, the term “ester” refers to carboxylate (—CO—O—),phosphonate (PO—(OR)—O—) or to thioesters (—SO—O—) groups. In oneembodiment, the term “reverse ester” refers to the reverse of the estergroups for example: —O—CO—.

In another embodiment, the present invention provides process forpreparing a selective androgen receptor modulator (SARM) compoundrepresented by the structure of formula III:

wherein

-   -   X is a bond, O, CH₂, NH, Se, PR, NO or NR;    -   G is O or S;    -   T is OH, OR, —NHCOCH₃, or NHCOR;    -   R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂,        CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl or OH;    -   R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃;    -   R₂ is H, F, Cl, Br, I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃,        NHCOR, alkyl, arylalkyl, OR, NH₂, NHR, N(R)₂, SR;    -   R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR, CF₃, Sn(R)₃,        or    -   R₃ together with the benzene ring to which it is attached forms        a fused ring system represented by the structure:    -   Z is NO₂, CN, Cl, F, Br, I, H, COR, COOH, or CONHR;    -   Y is CF₃, alkoxy, alkyl, hydroxyalkyl, alkylaldehyde, formyl, H,        F, Br, Cl, I, CN, or Sn(R)₃;    -   Q is H, alkyl, halogen, CF₃, CN CR₃, Sn(R)₃, N(R)₂, NHCOCH₃,        NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,        NHCSCF₃, NHCSR NHSO₂CH₃, NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R,        SR; or Q together with the benzene ring to which it is attached        is a fused ring system represented by structure A, B or C:    -   n is an integer of 1-4; and    -   m is an integer of 1-3;

the process comprising the step of coupling a compound of formula (10):

wherein Z, Y, G, R₁, T, R₃ and m are as defined above and L is a leavinggroup, with a compound of formula II:

wherein Q, X, R₂ and n are as defined above.

In one embodiment, the coupling step is carried out in the presence of abase. In another embodiment, the leaving group L is Br.

In another embodiment, the compound of formula 10 is prepared by:a) preparing a compound of formula 13 by ring opening of a cycliccompound of formula 12:

wherein L, R₁, G and T are as defined above, and T₁ is O or NH; andb) reacting an amine of formula 14:

wherein Z, Y, R₃ and m are as defined above, with the compound offormula 13, in the presence of a coupling reagent, to produce thecompound of formula 10.

It is understood to a person skilled in the art that when T₁ is O or NH,T in compound 13 is O or NH₂. Thus, when T in compound 13 is OR, thereaction will involve a further step of converting the OH to OR by areaction with, for example, an alkyl halide R—X. When T in compound 13is NHCOR, NHCOCH₃, the reaction will involve a further step ofconverting the NH₂ to NHCOR or NHCOCH₃, by a reaction with, for example,the corresponding acyl chloride ClCOR or ClCOCH₃.

In one embodiment, step (a) is carried out in the presence of HBr.

In one embodiment, whereby compound 13 of step (a) is reacted with acoupling agent prior to step (b).

In one embodiment, the coupling step is carried out in the presence of abase. In another embodiment, the leaving group L is Br.

In another embodiment, the process further comprises the step ofconverting the selective androgen receptor modulator (SARM) compound toits analog, isomer, metabolite, derivative, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, N-oxide,hydrate or any combination thereof.

In another embodiment, this invention provides a large scale process forthe preparation of compound of formula III, wherein the processcomprises the same steps as described herein above, wherein compound offormula 12 is prepared according to the following scheme, in thepresence of 4N NaOH:

FIGS. 1K and 1L provide one embodiment of a large scale process for thepreparation of a large scale synthesis of compounds of formulas S-II.

In one embodiment, the present invention provides a process forpreparing a compound of formula III wherein is X is O. In anotherembodiment, the present invention provides a process for preparing acompound of formula III wherein is T is OH. In another embodiment, thepresent invention provides a process for preparing a compound of formulaIII wherein is R₁ is CH₃. In another embodiment, the present inventionprovides a process for preparing a compound of formula III wherein Z isCN, and/or Cl and/or F. In another embodiment, the present inventionprovides a process for preparing a compound of formula III, wherein Z isCN. In another embodiment, the present invention provides a process forpreparing a compound of formula III wherein Y is CF₃ and/or CH₃, and/orH and/or Cl. In another embodiment, the present invention provides aprocess for preparing a compound of formula III wherein R₃ is H, and/orCN, and/or Cl and/or F. In another embodiment, the present inventionprovides a process for preparing a compound of formula III wherein Q isCN. In another embodiment, the present invention provides a process forpreparing a compound of formula III wherein Q is F. In anotherembodiment, the present invention provides a process for preparing acompound of formula III wherein Q is Cl.

In another embodiment, the present invention provides a process forpreparing a selective androgen modulator compound represented by thestructure of formula I:

wherein Q₂ is hydrogen, alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃,N(R)₂, NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR; andR is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃,CF₂CF₃, aryl, phenyl, F, Cl, Br, I, alkenyl or OH;

In another embodiment, the present invention provides a process forpreparing a selective androgen modulator compound represented by thestructure of formula U, as depicted in FIG. 1 and Example 1:

In another embodiment, the present invention provides a process forpreparing an (S) enantiomer of SARM compound represented by thestructure of formula II:

said process comprising the steps of:a) coupling an amine of formula 17:

with the carboxylic acid of formula R-18

in the presence of a coupling reagent, to produce an amide of formulaR-19

b) reacting the amide of formula R-19 with a compound of formula 20:

wherein Q is Cl or CN;

to produce a compound of formula S-II.

In one embodiment, whereby compound R-18 of step (a) is reacted with acoupling agent prior to addition of compound of formula 17.

FIG. 1A and Example 1 provide one embodiment of a process for thepreparation of a compound of formula S-II.

In another embodiment, the conditions of step (b) of the processoutlined hereinabove may comprise potassium carbonate, sodium carbonate,or cesium carbonate, or another base appropriate for this reaction,using 2-propanol, THF or methylethylketone as a solvent, optionally witha transition catalyst, BTBAC (benzyltributylammonium chloride) or othersuitable agent.

In another embodiment, the present invention provides a process forpreparing an (R) enantiomer of SARM compound represented by thestructure of formula R-II:

said process comprising the steps of:a) coupling an amine of formula 17:

with the carboxylic acid of formula S-18

in the presence of a coupling reagent, to produce an amide of formulaS-19

b) reacting the amide of formula S-19 with a compound of formula 20

to produce a compound of R-II.

In one embodiment, whereby compound S-18 of step (a) is reacted with acoupling agent prior to addition of compound of formula 17

FIG. 1B depicts one embodiment of such a process for the preparation ofcompound of formula R-II.

In another embodiment, the conditions of step (b) of the processoutlined hereinabove may comprise potassium carbonate, sodium carbonate,or cesium carbonate, or another base appropriate for this reaction,using 2-propanol, THF or methylethylketone as a solvent, optionally witha transition catalyst, BTBAC (benzyltributylammonium chloride) or othersuitable agent.

In another embodiment, the present invention provides a process forpreparing an (S) enantiomer of a SARM compound represented by thestructure of formula S-II

said process comprising the steps of:a) coupling an amine of formula 17:

with the carboxylic acid of formula R-18

in the presence of a coupling reagent, to produce an amide of formulaR-19

b) reacting the amide of formula R-19, with a base to form an oxiraneS-21

c) reacting the oxirane of formula S-21 with a compound of formula 20:

to produce a compound of S-II.

In one embodiment, whereby compound R-18 of step (a) is reacted with acoupling agent prior addition of compound of formula 17

FIG. 1C depicts an embodiment of such a process for the preparation ofcompound of formula S-II.

In another embodiment, the present invention provides a process forpreparing an (R) enantiomer of SARM compound represented by thestructure of formula R-II:

said process comprising the steps of:a) coupling an amine of formula 17:

with the carboxylic acid of formula S-18

in the presence of a coupling reagent, to produce an amide of formulaS-19

b) reacting the amide of formula S-19, with a base to form an oxiraneR-21

c) reacting the oxirane of formula R-21 with a compound of formula 20;

to produce a compound of R-II.

In one embodiment, whereby compound S-18 of step (a) is reacted with acoupling agent prior to addition of compound of formula 17.

FIG. 1D preparation of compound of formula R-II.

In another embodiment, the present invention provides a process forpreparing an (S) enantiomer of a SARM compound represented by thestructure of formula S-II.

said process comprising the steps of:

a) reacting a ring of formula S-22

with a compound of 20

to produce a compound of formula R-23;

a) ring opening of compound of formula R-23 to produce a compound offormula S-24

coupling the carboxylic acid of compound of formula S-24 with the amineof formula 17

to produce the compound of formula S-II.

FIG. 1E depicts an embodiment of such a process for the preparation ofcompound of formula S-II.

In another embodiment, the present invention provides a process forpreparing an (R) enantiomer of a SARM compound represented by thestructure of formula R-II:

said process comprising the steps of:

a) reacting a ring of formula R-22

with a compound of 20

to produce a compound of formula S-23;

b) ring opening of compound of formula S-23 to produce a compound offormula R-24

coupling the carboxylic acid of compound of formula R-24 with the amineof formula 17

to produce the compound of formula S-II.

FIG. 1F depicts an embodiment of such a process for the preparation ofcompound of formula S-II.

In another embodiment, the present invention provides a process forpreparing an (S) enantiomer of a SARM compound represented by thestructure of formula S-II

said process comprising the steps of:a) reacting the carboxylic acid of formula R-18

with tribromoacetaldehyde to produce a compound of formula R-25:

reacting the dioxalane derivative R-25 with a compound of formula 20

to produce a compound of formula R-26;

b) ring opening of compound of formula R-26 to produce a compound offormula S-24

coupling the carboxylic acid of compound of formula S-24 with the amineof formula 17:

to produce the compound of formula S-II.

FIG. 1G depicts an embodiment of such a process for the preparation ofcompound of formula S-II.

In another embodiment, the present invention provides a process forpreparing an (R) enantiomer of a SARM compound represented by thestructure of formula R-II

said process comprising the steps of:a) reacting the carboxylic acid of formula S-18

with tribromoacetaldehyde to produce a compound of formula S-25:

reacting the dioxalane derivative S-25 with a compound of formula 20

to produce a compound of formula S-26;

ring opening of compound of formula S-26 to produce a compound offormula R-24

coupling the carboxylic acid of compound of formula R-24 with the amineof formula 17:

to produce the compound of formula R-III.

FIG. 1H depicts an embodiment of such a process for the preparation ofcompound of formula R-II.

In another embodiment, the present invention provides a process forpreparing a racemic mixture of a SARM compound represented by thestructure of formula II

said process comprising the steps of:a) reacting a compound of formula 24

with a compound of formula 27

wherein P is selected from isocyanate (NCO) or isothiocyanate (NCS) toproduce a compound of formula 28a or 28b, respectively

b) ring opening of the oxazolidinedione or 2-thioxooxazolid-4-one ringof formula 28a or 28b in a presence of a base to produce a compound offormula III.

FIG. 1I depicts an embodiment of such a process for the preparation ofracemic compound of formula II.

In another embodiment, the present invention provides a process forpreparing a racemic mixture of a SARM compound represented by thestructure of formula II:

said process comprising the steps of:a) chlorinating methacrylic acid

b) coupling an 3-cyano 4-trifluoromethyl aniline of formula 17 withmethacryloyl chloride:

to produce the amide of formula 29.

c) oxidizing an amide of formula 29, to produce the oxirane of formula21

d) reacting the oxirane of formula 21 with a compound of formula 20

to produce the compound.

In another embodiment, the oxidizing an amide of formula 29 of step (c)comprises ozone. In another embodiment, the oxidizing agent is aperoxyacid, for example, peracetic acid, (CH₃COOOH). In anotherembodiment, the oxidizing agent meta-chloroperbenzoic acid (m-CPBA). Inanother embodiment, the oxidizing agent is Magnesium MonoPeroxyPthalicAcid (MMPP). In another embodiment, the oxidizing agent is hydrogenperoxide together with catalytic amounts (1.0-0.1 mol %) of manganese(2⁺) salts.

FIG. 1J depicts an embodiment of a process for the preparation ofracemic compound of formula II.

In one embodiment, this invention provides a process for preparing pureenantiomers of SARMs compounds of this invention, comprising the stepsof a) preparing a racemic SARM compound of this invention; and b)separating pure SARM compound of this invention from its racemicmixture.

In one embodiment, separation of the optically-active (R) isomer or (S)enantiomer, from the racemic SARM compounds of this invention comprisescrystallization techniques. In another embodiment, the crystallizationtechniques include differential crystallization of enantiomers. Inanother embodiment, the crystallization techniques include differentialcrystallization of diasteriomeric salts (tartaric salts or quininesalts). In another embodiment, the crystallization techniques includedifferential crystallization of chiral auxiliary derivatives (mentholesters, etc). In another embodiment, separation of the optically-active(R) isomer or (S) enantiomer, from the racemic SARM compounds of thisinvention comprises reacting the racemate mixture with another chiralgroup, forming of a diasteriomeric mixture followed by separation of thediasteriomers and removing the additional chiral group to obtain pureenantiomers. In another embodiment, separation of the optically-active(R) isomer or (S) enantiomer, from the racemic SARM compounds of thisinvention comprises chiral synthesis. In another embodiment, separationof the optically-active (R) isomer or (S) enantiomer, from the racemicSARM compounds of this invention comprises biological resolution. Inanother embodiment, separation of the optically-active (R) isomer or (S)enantiomer, from the racemic SARM compounds of this invention comprisesenzymatic resolution. In another embodiment, separation of theoptically-active (R) isomer or (S) enantiomer, from the racemic SARMcompounds of this invention comprises chromatographic separation using achiral stationary phase. In another embodiment, separation of theoptically-active (R) isomer or (S) enantiomer, from the racemic SARMcompounds of this invention comprises affinity chromatography. Inanother embodiment, separation of the optically-active (R) isomer or (S)enantiomer, from the racemic SARM compounds of this invention comprisescapillary electrophoresis. In another embodiment, separation of theoptically-active (R) isomer or (S) enantiomer, from the racemic SARMcompounds of this invention comprises forming an ester group of thehydroxyl group of the chiral carbon with an optically-active acid, forexample (−)-camphanic acid, separating the diastereomers esters, thusobtained, by fractional crystallization or preferably, byflash-chromatography, and then hydrolyzing each separate ester to thealcohol.

In another embodiment, the purity, and selectivity of an enantiomerobtained by the process of this invention, or by chiral separation of aracemic mixture of this invention can be determined by HPLC analysis.

In another embodiment, the process further comprises the step ofconverting the SARM compound to its analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate or any combination thereof.

According to this aspect of the invention, and in one embodiment, thereagent used for reacting the amide derivative, for example compound offormula 19 and the phenol derivative such as for example 20, or thecompound of formula 19 with the phenol of formula 30, or the compound offormula 37 together with the compound of formula 38 are carried out inthe presence of a base. Any suitable base that will deprotonate thehydrogen of the —XH moiety (for example, a phenol moiety when X is O)and allow the coupling may be used. Nonlimiting examples of bases arecarbonates such as alkali carbonates, for example sodium carbonate(Na₂CO₃), potassium carbonate (K₂CO₃) and cesium carbonate (Cs₂CO₃);bicarbonates such as alkali metal bicarbonates, for example sodiumbicarbonate (NaHCO₃), potassium bicarbonate (KHCO₃), alkali metalhydrides such as sodium hydride (NaH), potassium hydride (KH) andlithium hydride (LiH), and the like.

The leaving group L, according to this aspect, and in one embodiment,may comprise any removable group customarily considered for chemicalreactions, as will be known to the person skilled in the art. Suitableleaving groups are halogens, for example F, Cl, Br and I; alkylsulfonate esters (—OSO₂R) wherein R is an alkyl group, for examplemethanesulfonate (mesylate), trifluoromethanesulfonate, ethanesulfonate,2,2,2-trifluoroethanesulfonate, perfluoro butanesulfonate; arylsulfonate esters (—OSO₂Ar) wherein Ar is an aryl group, for examplep-toluoylsulfonate (tosylate), benzenesulphonate which may beunsubstituted or substituted by methyl, chlorine, bromine, nitro and thelike; NO₃, NO₂, or sulfate, sulfite, phosphate, phosphite, carboxylate,imino ester, N₂ or carbamate.

According to this aspect of the invention and in one embodiment, thereaction is carried out in a suitable inert solvent or diluent such as,for example, tetrahydrofuran, diethyl ether, acetone, methyl ethylketone, 2-propanol, aromatic amines such as pyridine; aliphatic andaromatic hydrocarbons such as benzene, toluene, and xylene;dimethylsulfoxide (DMSO), dimethylformamide (DMF), and dimethylacetamide(DMAC). In one embodiment, the reaction may be carried out in a suitableinert solvent or diluent as described hereinabove, suitably in thepresence of a base such as triethylamine, and at a temperature in therange, as described above. In one embodiment, the reaction may becarried out at an appropriate temperature, as will be known to oneskilled in the art, for example, in the range, of −20 to 120° C., or forexample at or near ambient temperature.

The coupling reagent defined hereinabove is a reagent capable of turningthe carboxylic acid/thiocarboxylic acid of formula 24 or 18 into areactive derivative thereof, thus enabling coupling with the respectiveamine to form an amide/thioamide bond. A suitable reactive derivative ofa carboxylic acid/thiocarboxylic acid is, for example, an acylhalide/thioacyl halide, for example an acyl/thioacyl chloride formed bythe reaction of the acid/thioacid and an inorganic acid chloride, forexample thionyl chloride; a mixed anhydride, for example an anhydrideformed by the reaction of the acid and a chloroformate such as isobutylchloroformate; an active ester/thioester, for example an ester formed bythe reaction of the acid and a phenol such as pentafluorophenol, anester such as pentafluorophenyl trifluoroacetate or an alcohol such asmethanol, ethanol, isopropanol, butanol or N-hydroxybenzotriazole; anacyl/thioacyl azide, for example an azide formed by the reaction of theacid/thioacid and azide such as diphenylphosphoryl azide; an acylcyanide/thioacyl cyanide, for example a cyanide formed by the reactionof an acid and a cyanide such as diethylphosphoryl cyanide; or theproduct of the reaction of the acid/thioacid and a carbodiimide such asdicyclohexylcarbodiimide.

It is to be understood that the process may comprise any embodimentdescribed herein, as will be appropriate to produce a SARM of acorresponding formula, as will be appreciated by one skilled in the art.

In one embodiment, the process for preparing a SARM of this inventionmay involve ring opening in the presence of less acidic conditions,which in another embodiment, diminish the likelihood of obtaining SARMcompound mixtures, and provide higher yield and purity of a SARM ofinterest. In one embodiment, the ring opening of a process as describedherein, to produce a carboxylic acid of formula 13, is carried out inthe presence of HBr, which, in one embodiment, is at a concentration ofup to 30%, or in another embodiment, of up to 40%, or in anotherembodiment, is of up to 25%, or in another embodiment, of up to 23%, orin another embodiment, of up to between 20-25%. In one embodiment, theSARMs of this invention may be produced via large-scale synthesis,providing highly pure products in high yields.

In one embodiment, the reaction may be carried out in a suitable inertsolvent or diluent as described hereinabove, suitably in the presence ofa base such as triethylamine, and at a temperature in the range, asdescribed above.

In some embodiments, the compounds as described herein are useful inpreventing and treating muscle wasting disorders, bone relateddisorders, and diabetes related disorders.

In some embodiments, the compounds as described herein are useful,either alone or as a composition, in males and females for the treatmentof a variety of hormone-related conditions, such as hypogonadism,sarcopenia, erectile dysfunction, lack of libido, osteoporosis andfertility. In some embodiments, the compounds as described herein areuseful in stimulating or promoting or restoring function to variousprocesses, which in turn result in the treatment of the conditions asherein described, including, inter aila, promoting erythropoiesis,osteogenesis, muscle growth, glucose uptake, insulin secretion, and/orpreventing lipidogenesis, clotting, insulin resistance, atherosclerosis,osteoclast activity, and others.

In one embodiment, the methods of this invention make use of thedescribed compound contacting or binding a receptor, and therebymediating the described effects. In some embodiments, the receptor is anuclear receptor, which in one embodiment, is an androgen receptor, orin another embodiment, is an estrogen receptor, or in anotherembodiment, is a progesterone receptor, or in another embodiment, is aglucocorticoid receptor. In some embodiments, the multitude of effectsmay occur simultaneously, as a function of binding to multiple receptorsin the subject. In some embodiments, the tissue selective effects of thecompounds as described herein provide for simultaneous action ondifferent target organs.

Pharmaceutical Compositions

In some embodiments, this invention provides methods of use whichcomprise administering a composition comprising the described compounds.As used herein, “pharmaceutical composition” means a “therapeuticallyeffective amount” of the active ingredient, i.e. the compound of FormulaI, together with a pharmaceutically acceptable carrier or diluent. A“therapeutically effective amount” as used herein refers to that amountwhich provides a therapeutic effect for a given condition andadministration regimen.

As used herein, the term “administering” refers to bringing a subject incontact with a compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humans.In one embodiment, the present invention encompasses administering thecompounds of the present invention to a subject.

The pharmaceutical compositions containing the compounds of thisinvention can be administered to a subject by any method known to aperson skilled in the art, such as orally, parenterally,intravascularly, paracancerally, transmucosally, transdermally,intramuscularly, intranasally, intravenously, intradermally,subcutaneously, sublingually, intraperitonealy, intraventricularly,intracranially, intravaginally, by inhalation, rectally, intratumorally,or by any means in which the recombinant virus/composition can bedelivered to tissue (e.g., needle or catheter). Alternatively, topicaladministration may be desired for application to mucosal cells, for skinor ocular application. Another method of administration is viaaspiration or aerosol formulation.

In one embodiment, the pharmaceutical compositions are administeredorally, and are thus formulated in a form suitable for oraladministration, i.e. as a solid or a liquid preparation. Suitable solidoral formulations include tablets, capsules, pills, granules, pellets,powders, and the like. Suitable liquid oral formulations includesolutions, suspensions, dispersions, emulsions, oils and the like. Inone embodiment of the present invention, the SARM compounds areformulated in a capsule. In accordance with this embodiment, thecompositions of the present invention comprise in addition to a compoundof this invention and the inert carrier or diluent, a hard gelatincapsule.

In one embodiment, the micronized capsules comprise particles containinga compound of this invention, wherein the term “micronized” used hereinrefers to particles having a particle size is of less than 100 microns,or in another embodiment, less than 60 microns, or in anotherembodiment, less than 36 microns, or in another embodiment, less than 16microns, or in another embodiment, less than 10 microns, or in anotherembodiment, less than 6 microns.

Further, in another embodiment, the pharmaceutical compositions areadministered by intravenous, intraarterial, or intramuscular injectionof a liquid preparation. Suitable liquid formulations include solutions,suspensions, dispersions, emulsions, oils and the like. In oneembodiment, the pharmaceutical compositions are administeredintravenously, and are thus formulated in a form suitable forintravenous administration. In another embodiment, the pharmaceuticalcompositions are administered intraarterially, and are thus formulatedin a form suitable for intraarterial administration. In anotherembodiment, the pharmaceutical compositions are administeredintramuscularly, and are thus formulated in a form suitable forintramuscular administration.

Further, in another embodiment, the pharmaceutical compositions areadministered topically to body surfaces, and are thus formulated in aform suitable for topical administration. Suitable topical formulationsinclude gels, ointments, creams, lotions, drops and the like. Fortopical administration, the compounds of this invention or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like are prepared and applied as solutions, suspensions, oremulsions in a physiologically acceptable diluent with or without apharmaceutical carrier.

Further, in another embodiment, the pharmaceutical compositions areadministered as a suppository, for example a rectal suppository or aurethral suppository. Further, in another embodiment, the pharmaceuticalcompositions are administered by subcutaneous implantation of a pellet.In a further embodiment, the pellet provides for controlled release of acompound as herein described over a period of time. In a furtherembodiment, the pharmaceutical compositions are administeredintravaginally.

In another embodiment, the active compound can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1627-1633(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.363-366 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid).

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

In one embodiment, the compositions of this invention may include, acompound of this invention or any combination thereof, together with oneor more pharmaceutically acceptable excipients.

It is to be understood that this invention encompasses any embodiment ofa compound as described herein, which in some embodiments is referred toas “a compound of this invention”. Such reference will include anycompound, which is characterized by a structure of the formulae I-XXII,or any embodiment thereof, as described herein.

Suitable excipients and carriers may be, according to embodiments of theinvention, solid or liquid and the type is generally chosen based on thetype of administration being used. Liposomes may also be used to deliverthe composition. Examples of suitable solid carriers include lactose,sucrose, gelatin and agar. Oral dosage forms may contain suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. Liquiddosage forms may contain, for example, suitable solvents, preservatives,emulsifying agents, suspending agents, diluents, sweeteners, thickeners,and melting agents. Parenteral and intravenous forms should also includeminerals and other materials to make them compatible with the type ofinjection or delivery system chosen. Of course, other excipients mayalso be used.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, cyclodextrins,emulsions or suspensions, including saline and buffered media. Examplesof oils are those of petroleum, animal, vegetable, or synthetic origin,for example, peanut oil, soybean oil, mineral oil, olive oil, sunfloweroil, and fish-liver oil.

Parenteral vehicles (for subcutaneous, intravenous, intraarterial, orintramuscular injection) include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's and fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers such as those based on Ringer's dextrose, andthe like. Examples are sterile liquids such as water and oils, with orwithout the addition of a surfactant and other pharmaceuticallyacceptable adjuvants. In general, water, saline, aqueous dextrose andrelated sugar solutions, and glycols such as propylene glycols orpolyethylene glycol are preferred liquid carriers, particularly forinjectable solutions. Examples of oils are those of petroleum, animal,vegetable, or synthetic origin, for example, peanut oil, soybean oil,mineral oil, olive oil, sunflower oil, and fish-liver oil.

In addition, the compositions may further comprise binders (e.g. acacia,cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropylcellulose, hydroxypropyl methyl cellulose, povidone), disintegratingagents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide,croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate),buffers (e.g., Tris-HCl., acetate, phosphate) of various pH and ionicstrength, additives such as albumin or gelatin to prevent absorption tosurfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acidsalts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate),permeation enhancers, solubilizing agents (e.g., cremophor, glycerol,polyethylene glycerol, benzlkonium chloride, benzyl benzoate,cyclodextrins, sobitan esters, stearic acids), anti-oxidants (e.g.,ascorbic acid, sodium metabisulfite, butylated hydroxyanisole),stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethylcellulose), viscosity increasing agents (e.g. carbomer, colloidalsilicon dioxide, ethyl cellulose, guar gum), sweetners (e.g. aspartame,citric acid), preservatives (e.g., Thimerosal, benzyl alcohol,parabens), coloring agents, lubricants (e.g. stearic acid, magnesiumstearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g.colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate,triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose,sodium lauryl sulfate), polymer coatings (e.g., poloxamers orpoloxamines), coating and film forming agents (e.g. ethyl cellulose,acrylates, polymethacrylates), and/or adjuvants.

In one embodiment, the pharmaceutical compositions provided herein arecontrolled release compositions, i.e. compositions in which the compoundof this invention is released over a period of time afteradministration. Controlled or sustained release compositions includeformulation in lipophilic depots (e.g. fatty acids, waxes, oils). Inanother embodiment, the composition is an immediate release composition,i.e. a composition in which all of the compound is released immediatelyafter administration.

In yet another embodiment, the pharmaceutical composition can bedelivered in a controlled release system. For example, the agent may beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit.Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:607 (1980);Saudek et al., N. Engl. J. Med. 321:674 (1989). In another embodiment,polymeric materials can be used. In yet another embodiment, a controlledrelease system can be placed in proximity to the therapeutic target,i.e., the brain, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 116-138 (1984). Other controlled release systems arediscussed in the review by Langer (Science 249:1627-1633 (1990).

The compositions may also include incorporation of the active materialinto or onto particulate preparations of polymeric compounds such aspolylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes,microemulsions, micelles, unilamellar or multilamellar vesicles,erythrocyte ghosts, or spheroplasts.) Such compositions will influencethe physical state, solubility, stability, rate of in vivo release, andrate of in vivo clearance.

Also comprehended by the invention are particulate compositions coatedwith polymers (e.g. poloxamers or poloxamines) and the compound coupledto antibodies directed against tissue-specific receptors, ligands orantigens or coupled to ligands of tissue-specific receptors.

Also comprehended by the invention are compounds modified by thecovalent attachment of water-soluble polymers such as polyethyleneglycol, copolymers of polyethylene glycol and polypropylene glycol,carboxymethyl cellulose, dextran, polyvinyl alcohol,polyvinylpyrrolidone or polyproline. The modified compounds are known toexhibit substantially longer half-lives in blood following intravenousinjection than do the corresponding unmodified compounds (Abuchowski etal., 1981; Newmark et al., 1982; and Katre et al., 1987). Suchmodifications may also increase the compound's solubility in aqueoussolution, eliminate aggregation, enhance the physical and chemicalstability of the compound, and greatly reduce the immunogenicity andreactivity of the compound. As a result, the desired in vivo biologicalactivity may be achieved by the administration of such polymer-compoundabducts less frequently or in lower doses than with the unmodifiedcompound.

The preparation of pharmaceutical compositions which contain an activecomponent is well understood in the art, for example by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients which are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the compounds of this invention or their physiologicallytolerated derivatives such as salts, esters, N-oxides, and the like aremixed with additives customary for this purpose, such as vehicles,stabilizers, or inert diluents, and converted by customary methods intosuitable forms for administration, such as tablets, coated tablets, hardor soft gelatin capsules, aqueous, alcoholic or oily solutions. Forparenteral administration, the compounds of this invention or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like are converted into a solution, suspension, or emulsion, ifdesired with the substances customary and suitable for this purpose, forexample, solubilizers or other.

An active component can be formulated into the composition asneutralized pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include the acid addition salts (formed with the freeamino groups of the polypeptide or antibody molecule), which are formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric, mandelic, andthe like. Salts formed from the free carboxyl groups can also be derivedfrom inorganic bases such as, for example, sodium, potassium, ammonium,calcium, or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

For use in medicine, the salts of the compound will be pharmaceuticallyacceptable salts. Other salts may, however, be useful in the preparationof the compounds according to the invention or of their pharmaceuticallyacceptable salts. Suitable pharmaceutically acceptable salts of thecompounds of this invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound according to theinvention with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid,maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid,citric acid, tartaric acid, carbonic acid or phosphoric acid.

In one embodiment, this invention provides pharmaceutical compositionscomprising a compound of this invention. In one embodiment, suchcompositions are useful for oral testosterone replacement therapy.

In one embodiment, this invention also provides a composition comprisingtwo or more compounds of this invention, or polymorphs, isomers,hydrates, salts, N-oxides, etc., thereof. The present invention alsorelates to compositions and a pharmaceutical compositions whichcomprises a compound of this invention alone or in combination with aprogestin or estrogen, or in another embodiment, chemotherapeuticcompound, osteogenic or myogenic compound, or other agents suitable forthe applications as herein described. In one embodiment, thecompositions of this invention will comprise a suitable carrier, diluentor salt.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inanother embodiment, the methods of this invention may compriseadministration of a compound of formula II of this invention at variousdosages In one embodiment, the compound of this invention isadministered at a dosage of 0.1-200 mg per day. In one embodiment, thecompound of this invention is administered at a dose of 0.1-10 mg, or inanother embodiment, 0.1-26 mg, or in another embodiment, 0.1-60 mg, orin another embodiment, 0.3-16 mg, or in another embodiment, 0.3-30 mg,or in another embodiment, 0.6-26 mg, or in another embodiment, 0.6-60mg, or in another embodiment, 0.76-16 mg, or in another embodiment,0.76-60 mg, or in another embodiment, 1-6 mg, or in another embodiment,1-20 mg, or in another embodiment, 3-16 mg, or in another embodiment,30-60 mg, or in another embodiment, 30-76 mg, or in another embodiment,100-2000 mg.

In one embodiment, the methods of this invention may compriseadministration of a compound of this invention at various dosages. Inanother embodiment, the methods of this invention may compriseadministration of a compound of formula II of this invention at variousdosages In one embodiment, the compound of this invention isadministered at a dosage of 1 mg. In another embodiment the compound ofthis invention is administered at a dosage of 6 mg, 10 mg, 16 mg, 20 mg,26 mg, 30 mg, 36 mg, 40 mg, 46 mg, 60 mg, 66 mg, 60 mg, 66 mg, 70 mg, 76mg, 80 mg, 86 mg, 90 mg, 96 mg or 100 mg.

In one embodiment, the present invention provides methods of usecomprising the administration of a pharmaceutical composition comprisinga) any embodiment of a compound as described herein; and b) apharmaceutically acceptable carrier or diluent; which is to beunderstood to include an analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, N-oxide, hydrate or any combinationthereof of a compound as herein described, and may comprise compounds offormula II.

In some embodiments, the present invention provides methods of use of apharmaceutical composition comprising a) any embodiment of the compoundsas described herein, including an analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate thereof or any combination thereof; b) apharmaceutically acceptable carrier or diluent; c) a flow-aid; and d) alubricant.

In another embodiment, the present invention provides methods of use ofa pharmaceutical composition comprising a) any embodiment of thecompounds as described herein, including an analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate thereof or any combination thereof; b) lactosemonohydrate; c) microcrystalline cellulose; d) magnesium stearate; ande) colloidal silicon dioxide.

In some embodiments, the methods of this invention make use ofcompositions comprising compounds of this invention, which offer theadvantage that the compounds are nonsteroidal ligands for the androgenreceptor, and exhibit anabolic activity in vivo. According to thisaspect, such compounds are unaccompanied by serious side effects,provide convenient modes of administration, and lower production costsand are orally bioavailable, lack significant cross-reactivity withother undesired steroid receptors, and may possess long biologicalhalf-lives.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

In one embodiment, the compositions for administration may be sterilesolutions, or in other embodiments, aqueous or non-aqueous, suspensionsor emulsions. In one embodiment, the compositions may comprise propyleneglycol, polyethylene glycol, injectable organic esters, for exampleethyl oleate, or cyclodextrins. In another embodiment, compositions mayalso comprise wetting, emulsifying and/or dispersing agents. In anotherembodiment, the compositions may also comprise sterile water or anyother sterile injectable medium.

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention, as described herein. In one embodiment, use of acompound of this invention or a composition comprising the same, willhave utility in inhibiting, suppressing, enhancing or stimulating adesired response in a subject, as will be understood by one skilled inthe art. In another embodiment, the compositions may further compriseadditional active ingredients, whose activity is useful for theparticular application for which the compound of this invention is beingadministered.

In some embodiments, the methods of this invention make use ofcompositions comprising compounds of this invention, which offer theadvantage that the compounds are nonsteroidal ligands for the androgenreceptor, and exhibit anabolic activity in vivo. According to thisaspect, such compounds are unaccompanied by serious side effects,provide convenient modes of administration, and lower production costsand are orally bioavailable, lack significant cross-reactivity withother undesired steroid receptors, and may possess long biologicalhalf-lives.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

In one embodiment, the compositions for administration may be sterilesolutions, or in other embodiments, aqueous or non-aqueous, suspensionsor emulsions. In one embodiment, the compositions may comprise propyleneglycol, polyethylene glycol, injectable organic esters, for exampleethyl oleate, or cyclodextrins. In another embodiment, compositions mayalso comprise wetting, emulsifying and/or dispersing agents. In anotherembodiment, the compositions may also comprise sterile water or anyother sterile injectable medium.

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention. In one embodiment, use of a compound of thisinvention or a composition comprising the same, will have utility ininhibiting, suppressing, enhancing or stimulating a desired response ina subject, as will be understood by one skilled in the art. In anotherembodiment, the compositions may further comprise additional activeingredients, whose activity is useful for the particular application forwhich the compound of this invention is being administered.

In some embodiments, the compositions will further comprise a5a-Reductase Inhibitors, a SARM or SARMs, a selective estrogen receptormodulator (SERM), an aromatase inhibitor, such as but not limited toanastrazole, exemestane, or letrozole; a GnRH agonist or antagonist, asteroidal or nonsteroidal GR ligand, a steroidal or nonsterodial PRligand, a steroidal or nonsteroidal AR antagonist, a17-aldoketoreductase inhibitor or 17b-hydroxysteroid dehydrogenaseinhibitor. Such compositions may be used, in some embodiments, fortreating a hormone dependent condition, such as, for example,infertility, neoplasia of a hormone-responsive cancer, for example, agonadal cancer, or a urogenital cancer.

In some embodiments, the composition will comprise the compounds asdescribed herein, as well as another therapeutic compound, includinginter alia, a SAR₁ such as finasteride, dutasteride, izonsteride; otherSARMs, such as, RU-58642, RU-56279, WS9761 A and B, RU-59063, RU-58841,bexlosteride, LG-2293, L-245976, LG-121071, LG-121091, LG-121104,LGD-2226, LGD-2941, YM-92088, YM-175735, LGD-1331, BMS-357597,BMS-391197, S-40503, BMS-482404, EM-4283, EM-4977, BMS-564929,BMS-391197, BMS-434588, BMS-487745, BMS-501949, SA-766, YM-92088,YM-580, LG-123303, LG-123129, PMCol, YM-175735, BMS-591305, BMS-591309,BMS-665139, BMS-665539, CE-590, 116BG33, 154BG31, arcarine, ACP-105;SERMs, such as tamoxifene, 4-hydroxytamoxifene, idoxifene, toremifene,ospemifene, droloxifene, raloxifene, arzoxifene, bazedoxifene, PPT(1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole), DPN, lasofoxifene,pipendoxifene, EM-800, EM-652, nafoxidine, zindoxifene, tesmilifene,miproxifene phosphate, RU 58,688, EM 139, ICI 164,384, ICI 182,780,clomiphene, MER-25, diethylstibestrol, coumestrol, genistein, GW5638,LY353581, zuclomiphene, enclomiphene, delmadinone acetate, DPPE,(N,N-diethyl-2-{4-(phenylmethyl)-phenoxy}ethanamine), TSE-424, WAY-070,WAY-292, WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, WAY-244,ERB-196, WAY-169122, MF-101, ERB-002, ERB-037, ERB-017, BE-1060, BE-380,BE-381, WAY-358, [18F]FEDNP, LSN-500307, AA-102, Ban zhi lian, CT-101,CT-102, VG-101; GnRH agonists or antagonists, such as, leuprolide,goserelin, triptorelin, alfaprostol, histrelin, detirelix, ganirelix,antide iturelix, cetrorelix, ramorelix, ganirelix, antarelix, teverelix,abarelix, ozarelix, sufugolix, prazarelix, degarelix, NBI-56418,TAK-810, acyline; FSH agonist/antagonist, LH agonist/antagonists,aromatase inhibitors, such as, letrozole, anastrazole, atamestane,fadrozole, minamestane, exemestane, plomestane, liarozole, NKS-01,vorozole, YM-511, finrozole, 4-hydroxyandrostenedione, aminogluethimide,rogletimide; Steroidal or nonsteroidal glucocorticoid receptor ligands,such as, ZK-216348, ZK-243149, ZK-243185, LGD-5552, mifepristone,RPR-106541, ORG-34517, GW-215864X, Sesquicillin, CP-472555, CP-394531,A-222977, AL-438, A-216054, A-276575, CP-394531, CP-409069, UGR-07;Steroidal or nonsterodial progesterone receptor ligands; Steroidal ornonsteroidal AR antagonists such as flutamide, hydroxyflutamide,bicalutamide, nilutamide, hydroxysteroid dehydrogenase inhibitors, PPAR□ligand such as bezafibrate, fenofibrate, gemfibrozil; PPARγ ligands suchas darglitazone, pioglitazone, rosiglitazone, isaglitazone,rivoglitazone, netoglitazone; Dual acting PPAR ligands, such asnaveglitazar, farglitazar, tesaglitazar, ragaglitazar, oxeglitazar,PN-2034, PPAR δ; a 17-ketoreductase inhibitors, 3β-DHΔ4,6-isomeraseinhibitors, 3β-DHΔ4,5-isomerase inhibitors, 17,20 desmolase inhibitors,p450c17 inhibitors, p450ssc inhibitors, 17,20-lyase inhibitors, orcombinations thereof.

In some embodiments, the compositions will further comprise Ghrelinreceptor ligand or growth hormone analogues and secretagogues, IGF-1,IGF-1 analogues and secretagogues, Myostatin Analogues, ProteasomeInhibitors, Androgenic/Anabolic Steroid, EnbrelMelanocortin 4 ReceptorAgonist, Insulins, or combinations thereof. Such compositions may beused, in some embodiments, for treating sarcopenia or a musculoskeletalcondition.

In some embodiments, the composition will comprise the copounds asdescribed herein, as well as another therapeutic compound, includinginter alia, Ghrelin receptor ligand or growth hormone analogues andsecretagogues, such as, pralmorelin, examorelin, tabimorelin,capimorelin, capromorelin, ipamorelin, EP-01572, EP-1572, JMV-1843, anandrogenic/Anabolic Steroid such as Testosterone/Oxandrolone; amelanocortin 4 receptor agonist, such as Bremelanotide, a Ghrelin oranalogue thereof, such as human ghrelin, CYT-009-GhrQb, L-692429,GHRP-6, SK&F-110679, U-75799E), leptin (metreleptin, pegylated leptin; aleptin receptor agonist, such as LEP (116-130), OB3, [D-Leu4]-OB3,rAAV-leptin, AAV-hOB, rAAVhOB; an insulin (short-, intermediate-, andlong acting formulations; a cortisol or corticosteroid, or a combinationthereof.

The invention contemplates, in some embodiments, administration ofcompositions comprising the individual agents, administered separatelyand by similar or alternative routes, formulated as appropriately forthe route of administration. The invention contemplates, in someembodiments, administration of compositions comprising the individualagents, administered in the same formulation. The inventioncontemplates, in some embodiments, staggered administration, concurrentadministration, of administration of the various agents over a course oftime, however, their effects are synergistic in the subject.

It is to be understood that any of the above means, timings, routes, orcombinations thereof, of administration of two or more agents is to beconsidered as being encompassed by the phrase “administered incombination”, as described herein.

In one embodiment, the compound of this invention is administered incombination with an anti-cancer agent. In one embodiment, theanti-cancer agent is a monoclonal antibody. In some embodiments, themonoclonal antibodies are used for diagnosis, monitoring, or treatmentof cancer. In one embodiment, monoclonal antibodies react againstspecific antigens on cancer cells. In one embodiment, the monoclonalantibody acts as a cancer cell receptor antagonist. In one embodiment,monoclonal antibodies enhance the patient's immune response. In oneembodiment, monoclonal antibodies act against cell growth factors, thusblocking cancer cell growth. In one embodiment, anti-cancer monoclonalantibodies are conjugated or linked to anti-cancer drugs, radioisotopes,other biologic response modifiers, other toxins, or a combinationthereof. In one embodiment, anti-cancer monoclonal antibodies areconjugated or linked to a SARM compound as described hereinabove.

In another embodiment, the present invention includes compounds andcompositions in which a compound of the invention is either combinedwith, or covalently bound to, an agent bound to a targeting agent, suchas a monoclonal antibody (e.g., a murine or humanized monoclonalantibody). In one embodiment, the agent bound to a targeting agent is acytotoxic agent. It will be appreciated that the latter combination mayallow the introduction of cytotoxic agents into for example cancer cellswith greater specificity. Thus, the active form of the cytotoxic agent(i.e., the free form) will be present only in cells targeted by theantibody. Of course, the compounds of the invention may also be combinedwith monoclonal antibodies that have therapeutic activity againstcancer.

In one embodiment, the compound is administered in combination with aselective tyrosine kinase inhibitor. In some embodiments, the selectivetyrosine kinase inhibitor inhibits catalytic sites of cancer promotingreceptors thereby inhibiting tumor growth. In one embodiment, aselective tyrosine kinase inhibitor modulates growth factor signaling.In some embodiments, the selective tyrosine kinase inhibitor targetsEGFR (ERB B/HER) family members. In one embodiment, the selectivetyrosine kinase inhibitor is a BCR-ABL tyrosine kinase inhibitor. In oneembodiment, the selective tyrosine kinase inhibitor is an epidermalgrowth factor receptor tyrosine kinase inhibitor. In one embodiment, theselective tyrosine kinase inhibitor is a vascular endothelial growthfactor tyrosine kinase inhibitor. In one embodiment, the selectivetyrosine kinase inhibitor is a Platelet Derived Growth Factor (PDGF)inhibitor.

In one embodiment, the compound is administered in combination with acancer vaccine. In one embodiment, the cancer vaccine is a therapeuticvaccine thus, treating an existing cancer. In some embodiments, thecancer vaccine is a prophylactic vaccine thus, preventing thedevelopment of cancer. In one embodiment, both types of vaccines havethe potential to reduce the burden of cancer. In one embodiment,treatment or therapeutic vaccines are administered to cancer patientsand are designed to strengthen the body's natural defenses againstcancers that have already developed. In one embodiment, therapeuticvaccines may prevent additional growth of existing cancers, prevent therecurrence of treated cancers, or eliminate cancer cells not killed byprior treatments. In some embodiments, prevention or prophylacticvaccines are administered to healthy individuals and are designed totarget cancer in individuals who present high risk for the disease. Inone embodiment, the cancer vaccine is an antigen/adjuvant vaccine. Inone embodiment, the cancer vaccine is a whole cell tumor vaccine. In oneembodiment, the cancer vaccine is a dendritic cell vaccine. In oneembodiment, the cancer vaccine comprises viral vectors and/or DNAvaccines. In one embodiment, the cancer vaccine is an idiotype vaccine.

In one embodiment, the compound is administered in combination with ananti-cancer chemotherapeutic agent. In one embodiment, the anti-cancerchemotherapeutic agent is an alkylating agent, such as but not limitedto cyclophosphamide. In one embodiment, the anti-cancer chemotherapeuticagent is a cytotoxic antibiotic such as but not limited to doxorubicin.In one embodiment, the anti-cancer chemotherapeutic agent is anantimetabolite, such as but not limited to methotrexate. In oneembodiment, the anti-cancer chemotherapeutic agent is a vinca alkaloid,such as but not limited to vindesine. In some embodiments, theanti-cancer chemotherapeutic agents include platinum compounds such asbut not limited to carboplatin, and taxanes such as docetaxel. In oneembodiment, the anti-cancer chemotherapeutic agent is an aromataseinhibitor such as but not limited to anastrazole, exemestane, orletrozole.

In one embodiment, the compound is administered in combination with aBax activity modulator such as alisol B acetate. In one embodiment, thecompound is administered in combination with an angiotensin II receptorblocker such as losartan. In one embodiment, the compound isadministered in combination with selenium, green tea cachecins, sawpalmetto, lycopene, vitamin D, dietary soy, genistein or isoflavone.

In one embodiment, the compound is administered in combination withantineoplastic agents, such as alkylating agents, antibiotics, hormonalantineoplastics and antimetabolites. Examples of useful alkylatingagents include alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines, such as a benzodizepa, carboquone, meturedepaand uredepa; ethylenimines and methylmelamines such as altretamine,triethylenemelamine, triethylenephosphoramide,triethylenethiophos-phoramide and trimethylolmelamine; nitrogen mustardssuch as chlorambucil, chlomaphazine, cyclophosphamide, estramustine,iphosphamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichine, phenesterine, prednimustine, trofosfamide, anduracil mustard; nitroso ureas, such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, ranimustine, dacarbazine,mannomustine, mitobronitol, mitolactol and pipobroman. More such agentswill be known to those having skill in the medicinal chemistry andoncology arts.

In some embodiments, other agents suitable for combination with thecompounds of this invention include protein synthesis inhibitors such asabrin, aurintricarboxylic acid, chloramphenicol, colicin E3,cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin,ethionine, fluoride, 5-fluorotryptophan, fusidic acid, guanylylmethylene diphosphonate and guanylyl imidodiphosphate, kanamycin,kasugamycin, kirromycin, and O-methyl threonine, modeccin, neomycin,norvaline, pactamycin, paromomycine, puromycin, ricin, α-sarcin, shigatoxin, showdomycin, sparsomycin, spectinomycin, streptomycin,tetracycline, thiostrepton and trimethoprim. Inhibitors of DNAsynthesis, including alkylating agents such as dimethyl sulfate,mitomycin C, nitrogen and sulfur mustards, MNNG and NMS; intercalatingagents such as acridine dyes, actinomycins, adriamycin, anthracenes,benzopyrene, ethidium bromide, propidium diiodide-intertwining, andagents such as distamycin and netropsin, can also be combined withcompounds of the present invention in pharmaceutical compositions. DNAbase analogs such as acyclovir, adenine, β-1-D-arabinoside,amethopterin, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine,azaserine, 6-azauracil, 2′-azido-2′-deoxynucliosides,5-bromodeoxycytidine, cytosine, β-1-D-arabinoside, diazooxynorleucine,dideoxynucleosides, 5-fluorodeoxycytidine, 5-fluorodeoxyuridine,5-fluorouracil, hydroxyurea and 6-mercaptopurine also can be used incombination therapies with the compounds of the invention. Topoisomeraseinhibitors, such as coumermycin, nalidixic acid, novobiocin and oxolinicacid, inhibitors of cell division, including colcemide, colchicine,vinblastine and vincristine; and RNA synthesis inhibitors includingactinomycin D, α-amanitine and other fungal amatoxins, cordycepin(3′-deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine,streptovaricin and streptolydigin also can be combined with thecompounds of the invention to provide pharmaceutical compositions.

In one embodiment, the compound is administered in combination with avaccine for prostate cancer, Alisol B acetate, angiotensin II receptorblocker, or others known in the art. In one embodiment, the compound isadministered in combination with an agent to decrease prostate (benignor malignant) hypertrophy, such as, for example, Selenium, green teacachecins, saw palmetto, lycopene, vitamin D, dietary soy, genistein andisoflavone food product and others.

In one embodiment, the compound is administered in combination with animmunomodulating agent. In one embodiment, the immunomodulating agent isan immunosuppressive agent. In one embodiment, immunosuppressive agentscomprise corticosteroids, cyclosporine, azathioprine, methotrexate,cyclophosphamide, tacrolimus —FK-506, anti-thymocyte globulin,mycophenylate moeftil, or a combination thereof. In one embodiment, thecorticosteroid is a glucocorticoid.

In one embodiment, the immunomodulating agent is an immunostimulatoryagent. In one embodiment, the immunostimulatory agent is a specificimmunostimulator thus, provides antigenic specificity during an immuneresponse, such as a vaccine or any antigen. In one embodiment, theimmunostimulatory agent is a non-specific immunostimulator thus, actingirrespective of antigenic specificity to augment immune response ofother antigen or stimulate components of the immune system withoutantigenic specificity. In one embodiment, the non-specificimmunostimulator is Freund's complete adjuvant. In one embodiment, thenon-specific immunostimulator is Freund's incomplete adjuvant. In oneembodiment, the non-specific immunostimulator is a montanide ISAadjuvant. In one embodiment, the non-specific immunostimulator is aRibi's adjuvant. In one embodiment, the non-specific immunostimulator isa Hunter's TiterMax. In one embodiment, the non-specificimmunostimulator is an aluminum salt adjuvant. In one embodiment, thenon-specific immunostimulator is a nitrocellulose-adsorbed protein. Inone embodiment, the non-specific immunostimulator is a Gerbu Adjuvant.

In one embodiment, the compound is administered in combination with anagent, which treats bone diseases, disorders or conditions, such asosteoporosis, bone fractures, etc., and this invention comprises methodsof treating the same, by administering the compounds as hereindescribed, alone or in combination with other agents.

In one embodiment, bone turnover markers have been demonstrated as aneffective, validated tool for the clinical scientist to monitor boneactivity. In another embodiment, urinary hydroxyproline, serum alkalinephosphatase, tartrate-resistant acid phosphatase, and osteocalcinlevels, along with the urinary calcium-creatinine ratio are used as boneturnover markers. In another embodiment osteocalcin levels is used as abone formation marker. In another embodiment c-telopeptide is used as abone resorption marker.

In one embodiment, this invention provides for the treatment,prevention, suppression or inhibition of, or the reduction of the riskof developing a skeletal-related event (SRE), such as bone fractures,surgery of the bone, radiation of the bone, spinal cord compression, newbone metastasis, bone loss, or a combination thereof in a subject withcancer, comprising administering to the a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, or anycombination thereof. The invention relates, inter alia to treatment ofan SRE with the compound of this invention in a subject with prostatecancer undergoing or having undergone androgen deprivation therapy(ADT).

It is to be understood that reference to “a compound of this invention”,or a use thereof is to be considered to encompass use of any compound asherein described, including any embodiment thereof. It is to beconsidered to encompass all of compounds which may be characterized bythe structure of Formulae I-XXII.

In one embodiment, the skeletal-related events treated using the methodsprovided herein and/or utilizing the compositions provided herein, arefractures, which in one embodiment, are pathological fractures,non-traumatic fractures, vertebral fracture, non-vertebral fractures,morphometric fractures, or a combination thereof. In some embodiments,fractures may be simple, compound, transverse, greenstick, or comminutedfractures. In one embodiment, fractures may be to any bone in the body,which in one embodiment, is a fracture in any one or more bones of thearm, wrist, hand, finger, leg, ankle, foot, toe, hip, collar bone, or acombination thereof.

In another embodiment, the methods and/or compositions provided herein,are effective in treatment, prevention, suppression, inhibition orreduction of the risk of skeletal-related events such as pathologicfractures, spinal cord compression, hypercalcemia, bone-related pain, ortheir combination.

In another embodiment, the skeletal-related events sought to be treatedusing the methods provided herein and/or utilizing the compositionsprovided herein, comprise the necessity for bone surgery and/or boneradiation, which in some embodiments, is for the treatment of painresulting in one embodiment from bone damage, or nerve compression. Inanother embodiment, the skeletal-related events sought to be treatedusing the methods provided herein and/or utilizing the compositionsprovided herein, comprise spinal cord compression, or the necessity forchanges in antineoplastic therapy, including changes in hormonaltherapy, in a subject. In some embodiments, skeletal-related eventssought to be treated using the methods provided herein and/or utilizingthe compositions provided herein, comprise treating, suppressing,preventing, reducing the incidence of, or delaying progression orseverity of bone metastases, or bone loss. In one embodiment, bone lossmay comprise osteoporosis, osteopenia, or a combination thereof. In oneembodiment, skeletal-related events may comprise any combination of theembodiments listed herein.

In one embodiment, the methods provided herein and/or utilizing thecompositions provided herein, are effective in reducing metastases tothe bone, such as in terms of number of foci, the size of foci, or acombination thereof. According to this aspect of the invention and inone embodiment, provided herein is a method of preventing or inhibitingcancer metastasis to bone in a subject, comprising the step ofadministering to the subject a composition comprising toremifene,raloxifene, tamoxifen or an analogue, functional derivative, metaboliteor a combination thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, such metabolites may comprise ospemifene, fispemifeneor their combination. In one embodiment, the cancer is prostate cancer.

A person skilled in the art would readily recognize that changes in theantineoplastic therapy according to the methods provided herein,utilizing the compositions provided herein may be conducted as afunction of, or adjusted or varied as a function of, inter-alia, theseverity of the underlying disease, the source of the underlyingdisease, the extent of the patients' pain and source of the patients'pain, as well as the stage of the disease. The therapeutic changes mayinclude in certain embodiments, changes in the route of administration(e.g. intracavitarily, intraartiarly, intratumoraly etc.), forms of thecompositions administered (e.g. tablets, elixirs, suspensions etc.),changes in dosage and the like. Each of these changes are wellrecognized in the art and are encompassed by the embodiments providedherein.

In one embodiment, the skeletal-related events are a result of cancertherapy. In one embodiment, the skeletal-related events are a result ofhormone deprivation therapy, while in another embodiment, they are aproduct of androgen deprivation therapy (ADT).

In one embodiment, the compounds of this invention are useful inprevention or reversal of androgen-deprivation therapy (ADT) inducedside effects such as reduced muscle mass, reduced muscle strength,frailty, hypogonadism, osteoporosis, osteopenia, decreased BMD and/ordecreased bone mass.

In males, while the natural decline in sex-hormones at maturity (directdecline in androgens as well as lower levels of estrogens derived fromperipheral aromatization of androgens) is associated with the frailty ofbones, this effect is more pronounced in males who have undergoneandrogen deprivation therapy.

Such agents for combined use may comprise a SERM, as herein described, abisphosphonate, for example, alendronate, tiludroate, clodroniate,pamidronate, etidronate, alendronate, zolendronate, cimadronate,neridronate, minodronic acid, ibandronate, risedronate, homoresidronate,a calcitonin, for example, salmon, Elcatonin, SUN-8577, TJN-135; aVitamin D or derivative (ZK-156979); a Vitamin D receptor ligand oranalogues thereof, such as calcitriol, topitriol, ZK-150123, TEI-9647,BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299, DP-035, an estrogen, estrogenderivative, or conjugated estrogen; an antiestrogen, progestin,synthetic estrogen/progestin; a RANK ligand mAb, for example, denosumabor AMG162 (Amgen); an ανβ3 integrin receptor antagonist; an osteoclastvacuolar ATPase inhibitor; an antagonist of VEGF binding to osteoclastreceptors; a calcium receptor antagonist; PTh (parathyroid hormone) oranalogues thereof, PTHrP analogues (parathyroid hormone-relatedpeptide), Cathepsin K inhibitors (AAE581); Strontium ranelate; Tibolone;HCT-1026, PSK3471; Gallium maltolate; Nutropin AQ; Prostaglandins, p38protein kinase inhibitor; a bone morphogenetic protein; an inhibitor ofBMP antagonism, an. HMG-CoA reductase inhibitor, a Vitamin K orderivative, an antiresorptive, an Ipriflavone, a fluoride salt, dietarycalcium supplement, Osteoprotegerin, or any combination thereof. In oneembodiment, the combined administration of a SARM as herein described,Osteoprotegerin and parathyroid hormone is contemplated for treating anydisease, disorder or condition of the bone.

In one embodiment, the immunomodulating agent is an anti-inflammatoryagent. In one embodiment, the anti-inflammatory agent is a non-steroidalanti-inflammatory agent. In one embodiment, the non-steroidalanti-inflammatory agent is a cox-1 inhibitor. In one embodiment, thenon-steroidal anti-inflammatory agent is a cox-2 inhibitor. In oneembodiment, the non-steroidal anti-inflammatory agent is a cox-1 andcox-2 inhibitor. In some embodiments, non-steroidal anti-inflammatoryagents include but are not limited to aspirin, salsalate, diflunisal,ibuprofen, fenoprofen, flubiprofen, fenamate, ketoprofen, nabumetone,piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin,etodolac, ketorolac, oxaprozin, or celecoxib. In one embodiment, theanti-inflammatory agent is a steroidal anti-inflammatory agent. In oneembodiment, the steroidal anti-inflammatory agent is a corticosteroid.

In one embodiment, the immunomodulating agent is an anti-rheumaticagent. In one embodiment, the anti-rheumatic agent is a non-steroidalanti-inflammatory agent. In one embodiment, the anti-rheumatic agent isa corticosteroid. In one embodiment, the corticosteroid is prednisone ordexamethasone. In one embodiment, the anti-rheumatic agent is a diseasemodifying anti-rheumatic drug. In one embodiment, the disease modifyinganti-rheumatic drug is a slow-acting anti-rheumatic drug. In oneembodiment, the disease modifying anti-rheumatic drug is an antimalarialagent. In one embodiment, disease modifying anti-rheumatic drugs includebut are not limited to chloroquine, hydroxychloroquine, methotrexate,sulfasalazine, cyclosporine, azathioprine, cyclophosphamide,azathioprine, sulfasalazine, penicillamine, aurothioglucose, gold sodiumthiomalate, or auranofin. In one embodiment, the anti-rheumatic agent isan immunosuppressive cytotoxic drug. In one embodiment,immunosuppressive cytotoxic drugs include but are not limited tomethotrexate, mechlorethamine, cyclophosphamide, chlorambucil, orazathioprine.

In one embodiment, the compound is administered in combination with anantidiabetic agent. In one embodiment, the antidiabetic agent is asulfonylurea. In one embodiment, sulfonylureas include but are notlimited to tolbutamide, acetohexamide, tolazamide, chlorpropamide,glipizide, glyburide, glimepiride, or gliclazide. In one embodiment, theantidiabetic agent is a meglitinide. In one embodiment, meglitinidesinclude but are not limited to prandin or nateglinide. In oneembodiment, the antidiabetic agent is a biguanide. In one embodiment,biguanides include but are not limited to metformin. In one embodiment,the antidiabetic agent is a thiazolidinedione. In one embodiment,thiazolidinediones include but are not limited to rosiglitazone,pioglitazone, or troglitazone. In one embodiment, the antidiabetic agentis an alpha glucosidase inhibitor. In one embodiment, alpha glucosidaseinhibitors include but are not limited to miglitol or acarbose. In oneembodiment, the antidiabetic agent is PPARα/γ ligand,dipeptidylpeptidase 4 (DPP-4) inhibitor, SGLT (sodium-dependent glucosetransporter 1) inhibitor, or FBPase (fructose 1,6-bisphosphatase)inhibitor. In one embodiment, the antidiabetic agent is insulin. In oneembodiment, the insulin is rapid-acting insulin. In one embodiment, theinsulin is short-acting insulin. In one embodiment, the insulin isintermediate-acting insulin. In one embodiment, the insulin isintermediate- and short-acting insulin mixtures. In one embodiment, theinsulin is long-acting insulin. In one embodiment, the antidiabeticagents are inhibitors of fatty acid binding protein (aP2) such as thosedisclosed in U.S. Ser. No. 09/519,079 filed Mar. 6, 2000, glucagon-likepeptide-1 (GLP-1), and dipeptidyl peptidase IV (DPP4) inhibitors such asthose disclosed in WO 0168603, which are incorporated by reference.

In one embodiment, the compound is administered in combination with anagent treating the nervous system. In one embodiment, the agent treatingthe nervous system is an agent treating the autonomic nervous system. Inone embodiment, the agent treating the autonomic nervous system is anadrenomimetic drug. In one embodiment, the adrenomimetic drug is abeta-adrenoceptor agonist, alpha-adrenoceptor agonist, or a combinationthereof. In one embodiment, the adrenomimetic drug is a catecholamine.In one embodiment, adrenomimetic drugs include but are not limited toisoproterenol, norepinephrine, epinephrine, amphetamine, ephedrine, ordopamine. In one embodiment, the adrenomimetic drug is a directly actingadrenomimetic drug. In some embodiments, directly acting adrenomimeticdrugs include but are not limited to phenylephrine, metaraminol, ormethoxamine.

In one embodiment, the agent treating the autonomic nervous system is anadrenoceptor antagonist. In one embodiment, the adrenoceptor antagonistis a haloalkylamine, imidazoline, or quinazoline. In one embodiment,haloalkylamines include but are not limited to phenoxybenzamine. In oneembodiment, imidazolines include but are not limited to phentolamine ortolazoline. In one embodiment, quinazolines include but are not limitedto prazosine, terazosin, doxazosin, or trimazosin. In one embodiment,the adrenoceptor antagonist has a combined alpha and beta blockingactivity. In one embodiment, the combined alpha and beta blocking agentis labetalol, bucindolol, carvedilol, or medroxalol

In one embodiment, the agent treating the autonomic nervous system is acholinomimetic agent. In one embodiment, the cholinomimetic agent is adirect-acting parasympathomimetic drug. In one embodiment, direct-actingparasympathomimetic drugs include but are not limited to methacholine,pilocarpine, carbachol, or bethanechol.

In one embodiment, the agent treating the autonomic nervous system is acholinesterase inhibitor. In one embodiment, the cholinesteraseinhibitor is a quaternary ammonium agent. In one embodiment, quaternaryammonium agents include but are not limited to edrophonium orambenonium. In one embodiment, the cholinesterase inhibitor is acarbamate such as physostigmine, pyridostigmine, neostigmine, orrivastigmine. In one embodiment, the cholinesterase inhibitor is anorganophosphate agent. In one embodiment, the inhibitor targetsacetylcholine in the central nervous system such as tacrine, donepezil,or galanthamine.

In one embodiment, the agent treating the autonomic nervous system is amuscarinic blocking agent. In one embodiment, the muscarinic blockingagent is a belladonna alkaloid such as atropine or scopolamine.

In one embodiment, the agent treating the autonomic nervous system is agangilionic blocking agent. In one embodiment, gangilionic blockingagents include but are not limited to nicotine, trimethaphan, ormecamylamine.

In one embodiment, the agent treating the nervous system is an agenttreating the central nervous system. In one embodiment, the agenttreating the central nervous system is a local anesthetic agent. In oneembodiment, local anesthetic agents include but are not limited tobenzocaine, chloroprocaine, cocaine, procaine, bupivacaine,levobupivacaine, lidocaine, mepivacaine, prilocalne, or ropivacaine. Inone embodiment, the agent treating the central nervous system is ageneral anaesthetic agent. In one embodiment, general anesthetic agentsinclude but are not limited to esflurane, sevoflurane, isoflurane,halothane, enflurane, methoxyflurane, xenon, propofol, etomidate,methohexital, midazolam, diazepamor, ketamine, thiopentone/thiopental,or lidocaine/prilocalne.

In one embodiment, the agent treating the central nervous system is ananalgesic agent. In some embodiments, analgesic agents include but arenot limited to paracetamol or non-steroidal anti-inflammatory agent. Insome embodiments, analgesic agents include opiates or morphinomimeticssuch as morphine, pethidine, oxycodone, hydrocodone, diamorphine,tramadol, or buprenorphine. In some embodiments, a combination of two ormore analgesics is desired.

In one embodiment, the agent treating the central nervous system is amuscle relaxant or vasoconstrictor agent. In one embodiment, musclerelaxants include but are not limited to methocarbamol, baclofen,carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone,orphenadrine, amyl nitrite, pancuronium, tizanidine, clonidine, orgabapentin. In one embodiment, vasoconstrictor agents include but arenot limited to antihistamines, adrenalin dimethylarginine, caffeine,cannabis, catecholamines, decongestants, pseudoephedrinse,norepinephrines, tetrahydrozoline, or thromboxane.

In one embodiment, the agent treating the central nervous system is anantiemetic drug. In one embodiment, the antiemetic drug is a 5-HT3receptor antagonist such as dolasetron, granisetron, ondansetron, ortropisetron. In one embodiment, the antiemetic drug is a dopamineantagonist such as domperidone droperidol, haloperidol, chlorpromazine,promethazine, or metoclopramide. In one embodiment, the antiemetic drugis an antihistamine such as cyclizine, diphenhydramine, dimenhydrinate,or meclizine. In one embodiment, the antiemetic drug is a cannabinoidsuch as cannabis or marinol.

In one embodiment, the agent treating the central nervous system is asedative agent. In one embodiment, the sedative agent is anantidepressant agent such as mirtazapine or trazodone. In oneembodiment, the sedative agent is a barbiturate such as secobarbital,pentobarbital, or amobarbital. In one embodiment, the sedative agent isa benzodiazepine such as diazepam, clonazepam, alprazolam, temazepam,chlordiazepoxide, flunitrazepam, lorazepam, or clorazepate. In oneembodiment, the sedative agent is an imidazopyridines such as zolpidemor alpidem. In one embodiment, the sedative agent is aPyrazolopyrimidine such as zaleplon. In one embodiment, the sedativeagent is an antihistamine such as diphenhydramine, dimenhydrinate, ordoxylamine. In one embodiment, the sedative agent is an antipsychoticagent such as ziprasidone, risperidone, quetiapine, clozapine,prochlorperazine, perphenazine, loxapine, trifluoperazine, thiothixene,haloperidol, or fluphenazine. In one embodiment, the sedative agent isan herbal sedative such as valerian plant mandrake, or kava. In someembodiments, the sedative agent is eszopiclone, ramelteon, methaqualone,ethchlorvynol, chloral hydrate, meprobamate, glutethimide, methyprylon,gamma-hydroxybutyrate, ethyl alcohol, methyl trichloride, zopiclone, ordiethyl ether.

In one embodiment, the agent treating the central nervous system is aneurodegenerative disorder medication. In one embodiment, theneurodegenerative disorder medication is an acetylcholinesteraseinhibitor such as tacrine, donepezil, galanthamine, or rivastigmine. Inone embodiment, the neurodegenerative disorder medication is anN-methyl-D-aspartate (NMDA) antagonist such as memantine. In oneembodiment, the neurodegenerative disorder medication reduces damage tomotor neurons such as riluzole. In one embodiment, the neurodegenerativedisorder medication silences the gene that causes the progression of thedisease. In one embodiment, the agent treating the central nervoussystem is an antiepileptic drug (AED). In some embodiments,antiepileptic agents include sodium channel blockers, GABA receptoragonists, GABA reuptake inhibitors, GABA transaminase inhibitor, AEDswith a potential GABA mechanism of action, glutamate blockers, or AEDswith other mechanisms of action. In some embodiments, antiepilepticagents include but are not limited to carbamazepine, fosphenyloin,oxcarbazepine, lamotrigine, zonisamide, clobazam, clonazepam,phenobarbital, primidone, tiagabine, vigabatrin, gabapentin, valproate,felbamate, topiramate, levetiracetam, or pregabalin.

In one embodiment, the agent treating the central nervous system is ananti-addiction drug. In one embodiment, the anti-addiction is ananti-alcoholism drug such as disulfuram. In one embodiment, theanti-addiction drug is a serotonin uptake inhibitor, dopaminergicagonist, or opioid antagonist.

In one embodiment, the agent treating the central nervous system is anagent treating Alzheimer disease. In some embodiments, agents treatingAlzheimer's disease include but are not limited to a cholinesteraseinhibitor, gamma secreatse inhibitor, or a beta lowering drug.

In one embodiment, the agent treating the central nervous system is anagent treating mild cognitive impairment. In some embodiments, agentstreating mild cognitive impairment include but are not limited to anAMPA regulator.

In one embodiment, the agent treating the central nervous system is anagent treating Parkinson's disease. In some embodiments, agents treatingParkinson's disease include but are not limited to a dopaminergic drugs,amantadine, benztropine, biperiden, bromocriptine, entacapone,carbidopa/levodopa, selegiline/deprenyl, iphenhydramine, pergolide,procyclidine, selegiline, or trihexyphenidyl.

In one embodiment, the compound is administered with an agent, whichtreats Alzheimer's disease, such as cholinesterase inhibitors, gammasecreatse inhibitors, A-beta lowering drugs; or an agent, which treatsmild cognitive impairment (MCI)—such as AMPA regulators, or an agent,which treats Parkinson's Disease, such as dopaminergic drugs, or anagent, which treats Major Depression, such as SSRI's, SNRI's, forexample, duloxetine, or an agent, which treats sexual dysfunction, suchas PDE5 inhibitors.

In one embodiment, the compound is administered in combination with anagent treating the cardiovascular system. In one embodiment, the agenttreating the cardiovascular system is treating a congestive heartfailure. In one embodiment, the agent treating congestive heart failureis an angiotensin converting enzyme (ACE) inhibitor such as benazepril,captopril, cilazapril, enalapril, fosinopril, lisinopril, moexipril,perindopril, quinapril, ramipril, trandolapril, or enalaprilat. In oneembodiment, the agent treating congestive heart failure is abeta-blocker such as acebutolol, atenolol, betaxolol hydrochloride,bisoprolol fumarate, carteolol hydrochloride, carvedilol, celiprololhydrochloride, esmolol hydrochloride, labetalol hydrochloride,levobunolol, metoprolol tartrate, metipranolol, nadolol, nebivolol,oxprenolol hydrochloride, pindolol, propranolol hydrochloride, sotalolhydrochloride, or timolol maleate. In one embodiment, the agent treatingcongestive heart failure is digoxin. In one embodiment, the agenttreating congestive heart failure is a diuretic such as thiazidediuretic, loop diuretic, potassium-sparing diuretic, or a combinationthereof. In some embodiments, thiazide diuretics include but are notlimited to bendrofluazide, bendroflumethiazide, benzthiazide,chlorothiazide, chlorthalidone, cyclopenthiazide, Diucardin®, Diuril®,Enduron®, Esidrix®, Exna®, HCTZ, Hydrochlorothiazide, HydroDIURIL®,HYDROFLUMETHLAZIDE, Hydromox®, Hygroton®, indapamide, Lozol®,methyclothiazide, metolazone, Mykrox®, Naqua®, Naturetin®, Oretic®,polythiazide, quinethazone, Renese®, trichlormethiazide, xipamide, orZaroxolyn®. In some embodiments, loop diuretics include but are notlimited to furosemide/frusemide, bumetanide, or torasemide. In someembodiments, potassium-sparing diuretics include but are not limited toamiloride, triamterene, aldosterone antagonists, or spironolactone.

In one embodiment, the agent treating the cardiovascular system is ananti-arrhythmic agent. In one embodiment, the anti-arrhythmic agent is asodium channel blocker, beta-adrenergic blocker, calcium channelblocker, or an agent that prolong repolarization. In one embodiment,sodium channel blockers include but are not limited to quinidine,procainamide, disopyramidei, lidocaine, tocamide, mexiletine, encamide,or flecamide. In one embodiment, beta-adrenergic blockers include butare not limited to propranolol, acebutolol, esmolol, or sotalol. In oneembodiment, agents that prolong repolarization include but are notlimited to sotalol or amiodarone. In one embodiment, calcium channelblockers include but are not limited to verapamil, diltiazem,nifedipine, or mebefradil. In one embodiment, the anti-arrhythmic agentis adenosine or digoxin.

In one embodiment, the agent treating the cardiovascular system is ananti-anginal agent. In one embodiment, the anti-anginal agent is anantiplatelet agent, adrenoceptor antagonist, calcium channel blocker, ora vasodilator. In some embodiments, the adrenoceptor antagonists andcalcium channel blockers comprise agents as described hereinabove. Inone embodiment, the antiplatelet agent is a cyclooxygenase inhibitor,ADP inhibitor, phosphodiesterase (I) inhibitor, glycoprotein IIb/IIIainhibitor, or an adenosine reuptake inhibitor. In one embodiment,cyclooxygenase inhibitors include but are not limited to acetylsalicylicacid or an acetylsalicylic acid in combination with dipyridimole. In oneembodiment, ADP inhibitors include but are not limited to clopidogrel,CS-747, or ticlopdipine. In one embodiment, phosphodiesterase IIIinhibitors include but are not limited to cilostazol. In one embodiment,glycoprotein IIb/IIIa inhibitors include but are not limited toabciximab, rheopro, eptifibatide, integrilin, tirofiban, or aggrastat.In one embodiment, adenosine reuptake inhibitors include but are notlimited to dipyridimole. In one embodiment, vasodilator agents includebut are not limited to isosorbide dinitrate, isosorbide mononitrate, ornitroglycerine. In one embodiment, cardiac glycosides such as digitalisor ouabain may be used in combination with a SARM compound.

In one embodiment, the agent treating the cardiovascular system is avasocative agent or an inotrope. In one embodiment, vasocative agents orinotropes include but are not limited to digoxin, dopamine, dobutamine,hydralazine, prazosin, carvedilol, nitroprusside, nitroglycerin,captopril, lisinopril, nifedipine, diltiazem, hydrochlorothiazide,furosemide, spironolactone, AT-1 receptor antagonists (e.g., losartan,irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan,atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidaseinhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat andgemopatrilat), or nitrates.

In one embodiment, the agent treating the cardiovascular system is ananticoagulant agent. In one embodiment, the anticoagulant agent is acoumarin derivative or an unfractionated heparin. In one embodiment,coumarin derivatives include but are not limited to warfarin.

In one embodiment, the agent treating the cardiovascular system is afibrinolytic agent such as streptokinase, urokinase, alteplase,anistreplase, prourokinase, reteplase, tenecteplase, lanoteplase,staphylokinase, vampire, or alfimeprase.

In one embodiment, the agent treating the cardiovascular system is ahypercholesterolemic agent such as niacin-lovastatin, colestipol HCl,fluvastatin sodium, atorvastatin calcium, simvastatin, gemfibrozil,lovastatin, pravastatin sodium, cholestyramine, cholestyramine light,fenofibrate, colesevelam HCl, or ezetimibe.

In one embodiment, the SARM compound is administered in combination withan agent treating the gastrointestinal system. In one embodiment, theagent treating the gastrointestinal (GI) system is enhancing GImotility. In one embodiment, the agent enhancing GI motility is aprokinetic agent such as metoclopramide, cisapride, tegaserod, orerythromycin. In one embodiment, the agent treating the GI system isdecreasing GI motility. In one embodiment, the agent decreasing GImotility is an opioid such as morphine, diphenoxylate, loperamidehydrochloride, or opium.

In one embodiment, the agent treating the GI system is an adsorbent or abulking agent. In one embodiment, the adsorbent is kaolin or otherhydrated aluminum silicate clays. In one embodiment, the hydratedaluminum silicate clay is further combined with pectin. In oneembodiment, adsorbents or bulking agents comprise bismuth subsalicylate,methylcellulose, psyllium derivative, or calcium polycarbophil.

In one embodiment, the agent treating the GI system is a stool softener.In one embodiment, stool softeners include but are not limited tomineral oil, docusate dioctyl sodium sulfosuccinate, dioctyl calciumsulfosuccinate, or dioctyl potassium sulfosuccinate.

In one embodiment, the agent treating the GI system is a laxative. Inone embodiment, the agent treating the GI system is a bulk forminglaxative as described hereinabove. In one embodiment, the laxative is anosmotic laxative such as lactulose, sorbitol, or polyethylene glycol. Inone embodiment, the laxative is a saline laxative such as milk ofmagnesia, magnesium citrate, sodium phosphate, docusate potassium,sorbitol, sodium phosphate-biphosphate, or visicoli.

In one embodiment, the agent treating the GI system is a catharticstimulant. In one embodiment, the cathartic stimulant is ananthraquinone dervative such as cascara, aloe, senna, or rhubarb. In oneembodiment, the cathartic stimulant is phenolphthalein, castor oil, orbisacodyl.

In one embodiment, the agent treating the GI system is an emetic agent.In one embodiment, the emetic agent is ipecac or apomorphine. In oneembodiment, the agent treating the GI system is an anti-emetic agentsuch as antihistamine, anti-cholinergic agent, benzodiazepine,cannabinoid, dopamine antagonist, phenothiazine derivative, or 5-HT3antagonist such as ondansetron or granisetron.

In one embodiment, the agent treating the GI system is an antacid. Inone embodiment the antacid pharmaceutical preparation comprisesbuffering agents such as sodium bicarbonate, calcium carbonate,magnesium hydroxide, or aluminum hydroxide.

In one embodiment, the agent treating the GI system is an H2-receptorantagonist. In some embodiments, the H2-receptor antagonist iscimetidine, ranitidine, famotidine, or nizatidine.

In one embodiment, the agent treating the GI system is a proton pumpinhibitor. In some embodiments, the proton pump inhibitor is omeprazole,lansoprazole, pantoprazole, rebeprazole, or esomeprazole.

In one embodiment, the agent treating the GI system is an agent treatinginflammation. In one embodiment, the agent treating inflammation is5-amino-salicylate, corticosteroid, metronidazole, ciprofloxacin,infiximab, budesonide, or anti-TNF alpha antibody.

In one embodiment, the compound is administered in combination with anagent treating a metabolic disease, disorder or condition, which in someembodiments refers to metabolic syndrome. In some embodiments, suchagents comprise, inter alia, pancreatic lipase inhibitors, such as forexample, orlistat, cetilistat, serotonin and norepinephrine reuptakeinhibitors, such as sibutramine, insulin-sensitizers such as biguanides(metformin) or PPAR agonists, dual-acting PPAR agonists (muraglitazar,tesaglitazar, naveglitazar), PPAR-delta agonists (GW-501516), DPP-IVInhibitors (vildagliptin, sitagliptin), alpha glucosidase inhibitors(acarbose), anti-diabetic combinations (ActoPlusMet, AvandaMet,metformin/pioglitazone, metformin/rosiglitazone, Glucovance, etc.),glucagon-like peptide-1 analogues (exenatide, liraglutide), amylinanalogues (pramlintide), statins (atorvastatin, simvastatin,rosuvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin),cholesterol absorption inhibitors (ezetimibe), nicotinic acidderivatives (immediate release and controlled release niacins, niaslo,etc.), antidyslipidemic fixed combinations (simvastatin/ezetimibe,lovastatin/nicotinic acid, atorvastatin/amlodipine,atorvastatin/torcetrapib, simvastatin/nicotinic acid (ER)), ACEinhibitors (ramipril, captopril, lisinopril), AT-II receptor antagonists(valsartan, telmisartan), cannabinoid receptor antagonists (rimonabant),cholesteryl ester transfer protein or CETP Inhibitors (JTT-705, CETi-1),beta3 adrenergic agonists, PPARa ligands, or combinations thereof.

In one embodiment, the compound is administered in combination with anagent treating a dermatological disorder. In one embodiment, the agenttreating a dermatological disorder is a corticosteroid orglucocorticosteroid such as betamethasone dipropionate, clobetasol,diflorasone, amcinonide, desoximetasone, fluocinonide, aclometasone,desonide triamcinolone, fluticasone, halobetasol, mometasone, orhydrocortisone. In one embodiment, the agent treating a dermatologicaldisorder is a retinoid such as isotretinoin, acitretin, tretinoin,adapalene, tazarotene, bexarotene, alitretinoin, or beta-carotene.

In one embodiment, the agent treating a dermatological disorder isphotochemotherapy agent. In one embodiment, the photochemotherapy agentis PUVA or psoralen such as oxsoralen. In one embodiment, the agenttreating a dermatological disorder is a photodynamic agent such asporphyrin.

In one embodiment, the agent treating a dermatological disorder isdaspone, thalidomide, anti-malarial agent, antimicrobial agent, orantifungal agent. In one embodiment, the anti-malarial agent ischloroquine or hydroxychloroquine.

In one embodiment, the agent treating a dermatological disorder is anantibiotic. In one embodiment, the antibiotic is a systemic antibioticsuch as griseofulvin, ketoconazole, fluconazole, itraconazole,terbinafine, or potassium iodide. In one embodiment, the antibiotic is atopical antifungal agent. In some embodiment, topical antifungal agentsinclude but are not limited to ciclopirox, clotrimazole, econazole,ketoconazole, miconazole, naftifine, oxiconazole, terbinafine, ortolnaftate.

In one embodiment, the agent treating a dermatological disorder is anantiviral agent such as interferon alpha. In one embodiment, the agenttreating a dermatological disorder is an antiscabies agent such aspyrethrin or pyrethroid. In one embodiment, the agent treating adermatological disorder is an immunosuppressive agent such asmycophenolate motefil or 6-thioguanine. In one embodiment, the agenttreating a dermatological disorder is a topical immunosuppressive agentsuch as tacrolimus, pimecrolimus, imiquimod, 5-fluorouracil, ormechlorethamine. In one embodiment, the agent treating a dermatologicaldisorder is an antihistamine such as doxepin. In one embodiment, theagent treating a dermatological disorder is treating pigmentation suchas hydroquinone or monobenzone. In one embodiment, the agent treating adermatological disorder is a protein or a recombinant protein such asbecaplermin, etanercept, denileukin diftitox, or botulinum toxin. In oneembodiment, the agent treating a dermatological disorder is capsaicin,anthralin, benzoyl peroxide, or calcipotriene.

In one embodiment, the agent treating a dermatological disorder is akeratolytic agent. In one embodiment, the agent treating adermatological disorder is selenium sulfide. In one embodiment, theagent treating or preventing a dermatological disorder is a sunscreen.In one embodiment, the sunscreen absorbs UVB, UVA, or a combinationthereof.

In one embodiment, the agent treating a dermatological disorder may be agrowth factor such as epidermal growth factor (EGF), transforming growthfactor-α (TGF-α), platelet derived growth factor (PDGF), fibroblastgrowth factors (FGFs) including acidic fibroblast growth factor (α-FGF)and basic fibroblast growth factor (β-FGF), transforming growth factorα(TGF-β) and insulin like growth factors (IGF-1 and IGF-2), or anycombination thereof.

In one embodiment, the compound is administered in combination with ananti-infective agent. In one embodiment, the anti-infective agent is anantibiotic agent. In one embodiment the antibiotic is a beta-lactamantibiotic. In one embodiment beta-lactam antibiotics include but arenot limited to penicillin, benzathine penicillin, benzylpenicillin,amoxicillin, procaine penicillin, dicloxacillin, amoxicillin,flucloxacillin, ampicillin, methicillin, aziocillin, carbenicillin,ticarcillin, mezlocillin, piperacillin, phenoxymethylpenicillin,co-amoxiclav, cephalosporin, cefalexin, cephalothin, cefazolin,cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceftriaxone,cefotaxime, ceftazidime, cefepime, cefpirome, imipenem, meropenem,ertapenem, faropenem, monobactam, aztreonam, or carbapenem.

In one embodiment the antibiotic is a tetracycline antibiotic. In oneembodiment tetracycline antibiotics include but are not limited totetracycline, chlortetracycline, demeclocycline, doxycycline,lymecycline, minocycline, or oxytetracycline.

In one embodiment the antibiotic is a macrolide antibiotic. In oneembodiment macrolide antibiotics include but are not limited toerythromycin, azithromycin, oxithromycin, dirithromycin, clarithromycin,josamycin, oleandomycin, kitasamycin, spiramycin, tylosin/tylocine,troleandomycin, carbomycin, cethromycin, or telithromycin.

In one embodiment the antibiotic is an aminoglycoside antibiotic. In oneembodiment, aminoglycoside antibiotics include but are not limited togentamicin, tobramycin, faropenem, imipenem, kanamycin, neomycin,ertapenem, apramycin, paromomycin sulfate, streptomycin, or amikacin.

In one embodiment the antibiotic is a quinolone antibiotic. In oneembodiment quinolone antibiotics include but are not limited tociprofloxacin, norfloxacin, lomefloxacin, enoxacin, ofloxacin,ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin,trovafloxacin, or alatrofloxacin.

In one embodiment the antibiotic is a cyclic peptide antibiotic. In oneembodiment cyclic peptide antibiotics include but are not limited tovancomycin, streptogramins, Microcin J25, Bacteriocin AS-48, RTD-1, orpolymyxins.

In one embodiment the antibiotic is a lincosamide antibiotic. In oneembodiment lincosamide antibiotics include but are not limited toclindamycin.

In one embodiment, the antibiotic is an oxazolidinone antibiotic. In oneembodiment oxazolidinone antibiotics include but are not limited tolinezolid, U-100592, DA-7867, AZD2563, or U-100766.

In one embodiment, the antibiotic is a sulfa antibiotic. In oneembodiment, sulfa antibiotics include but are not limited tosulfisoxazole.

In one embodiment, the antibiotic is an antiseptic agent. In oneembodiment, antiseptic agents include but are not limited to alcohols,chlorhexidine, chlorine, hexachlorophene, iodophors, chloroxylenol(PCMX), quaternary ammonium compounds, or triclosan.

In one embodiment, the antibiotic is an anti-tuberculosis agent. In oneembodiment an anti-tuberculosis agents include but are not limited toethambutol, rifabutin, isoniazid, rifampicin, pyrazinamide, or rifampin

In one embodiment, the antibiotic is an antifungal agent. In oneembodiment, antifungal agents include but are not limited toterbinafine, flucytosine, fluconazole, itraconazole, ketoconazole,ravuconazole, posaconazole, voriconazole, caspofungin, micafungin,v-echinocandin, amphotericin B, amphotericin B lipid complex (ABLC),amphotericin B colloidal dispersion (ABCD), liposomal amphotericin b(l-Amb), liposomal nystatin, or griseofulvin.

In one embodiment, the antibiotic is an antiprotozoal agent. In oneembodiment the antiprotozoal agent is an antimalarial agent. In oneembodiment, antimalarial agents include but are not limited tochloroquine, mefloquine, proguanil, pyrimethamine with dapsone,pyrimethamine with sulfadoxine, quinine, or primaquine. In oneembodiment, the antiprotozoal agent is an amoebicide. In one embodiment,amoebicides include but are not limited to metronidazole, timidazole, ordiloxanide furoate. In one embodiment, the antiprotozoal agent is anantigiadial agent. In one embodiment, antigiadial agents include but arenot limited to metronidazole, timidazole, or mepacrine. In oneembodiment, the antiprotozoal agent is a leishmanicide. In oneembodiment, leishmanicides include but are not limited to sodiumstibogluconate. In one embodiment, the antibiotic is an antithelminticagent.

In one embodiment, the antibiotic is an antiviral agent. In oneembodiment, antiviral agents include but are not limited to abacavir,acyclovir, amantadine, didanosine, emtricitabine, enfuvirtide,entecavir, lamivudine, nevirapine, oseltamivir, ribavirin, rimantadine,stavudine, valaciclovir, vidarabine, zalcitabine, or zidovudine. In oneembodiment, the antiviral agent is a nucleotide analog reversetranscriptase inhibitor. In one embodiment, nucleotide analog reversetranscriptase inhibitors include but are not limited totenofovir oradefovir. In one embodiment, the antiviral agent is a proteaseinhibitor. In one embodiment, protease inhibitors include but are notlimited to saquinavir, ritonavir, indinavir, nelfinavir, amprenavir,lopinavir, fosamprenavir, or tipranavir. In one embodiment, theantiviral agent is a fusion inhibitor such as enfuvirtide. In oneembodiment, a combination of antiviral or antiretroviral agents isdesired. In one embodiment, antiviral or antiretroviral agents or acombination thereof, further comprise hydroxyurea, resveratrol,grapefruit, ritonavir, leflunomide, or a combination thereof.

In one embodiment, the compound is administered in combination with anagent treating the liver. In one embodiment, the compound isadministered in combination with a statin. In some embodiment, statinsinclude but are not limited to atorvastatin, fluvastatin, lovastatin,pravastatin, simvastatin, or rosuvastatin.

In one embodiment, the compound is administered in combination with abile acid sequestrant. In some embodiment, bile acid sequestrantsinclude but are not limited to cholestyramine, colestipol, orcolesevelam.

In one embodiment, the compound is administered in combination with acholesterol absorption inhibitor. In some embodiment, cholesterolabsorption inhibitors include but are not limited to ezetimibe.

In one embodiment, the compound is administered in combination with anicotinic acid agent. In some embodiments, nicotinic acid agents includebut are not limited to niacin, niacor, or slo-niacin.

In one embodiment, the compound is administered in combination with afibrate. In some embodiments, fibrates include but are not limited togemfibrozil, or fenofibrate.

In one embodiment, the agent treating the liver is cortisone, cortisolor corticosterone. In some embodiments, the agent treating the liver iscolchicine, methotrexate, ursodeoxycholic acid, or penicillamine.

In one embodiment, the compound is administered in with an agenttreating the kidney. In one embodiment, the agent treating the kidney isa diuretic. In some embodiments, diuretics include but are not limitedto organomercurial, ethacrynic acid, frusemide, humetanide, piretanide,muzolimine, chlorothiazide and thiazide, phthalimidine, chlorthalidone,clorexolone, quinazolinone, quinethazone, metolazoneilenzenesulphonamide, mefruside, chlorobenzamide, clopamidesalicylamide,xipamide, xanthine, aminophylline, carbonic anhydrase inhibitor,acetazolamide mannitol, potassium-sparing compound, aldosteroneantagonist, spironolactone and canrenoate, pteridines, pyrazine,carboxamide-triamterene, or amiloride. In one embodiment, the agenttreating the kidney is a steroid.

In one embodiment, the agent treating the kidney is erythropoietin. Inone embodiment, erythropoietin is obtained by natural sources (e.g.,urinary erythropoietin; See U.S. Pat. No. 3,865,801), or is arecombinantly produced protein and analogs thereof, for example, asdescribed in U.S. Pat. Nos. 5,441,868, 5,547,933, 5,618,698 and5,621,080 as well as human erythropoietin analogs with increasedglycosylation and/or changes in the amino acid sequence as thosedescribed in European Patent Publication No. EP 668351 and thehyperglycosylated analogs having 1-14 sialic acid groups and changes inthe amino acid sequence described in PCT Publication No. WO 91/05867. Inone embodiment, erythropoietin-like polypeptides are administered incombination with the compounds of this invention. In some embodiments,erythropoietin-like polypeptides comprise darbepoietin (from Amgen; alsoknown as Aranesp and novel erthyropoiesis stimulating protein (NESP)).

In one embodiment, the SARM compound is administered in with an agenttreating a metabolic disease. In some embodiments, agents treating ametabolic disease include but are not limited to a vitamin, CoenzymeQ10, glucosidase alfa, sodium bicarbonate, bisphosphonate, biotin,allopurinol, levodopa, diazepam, phenobarbital, haloperidol, folic acid,antioxidants, activators of cation channels haptoglobin, or carnitine.

In one embodiment, the agent treating a metabolic disease is apancreatic lipase inhibitor such as orlistat or cetilistat, Serotonin ornorepinephrine reuptake inhibitor such as sibutramine,insulin-sensitizers such as biguanide, PPAR agonist, Dual-acting PPARagonist such as muraglitazar, tesaglitazar, or naveglitazar, PPAR-deltaagonist such as GW-501516, DPP-IV Inhibitor such as vildagliptin orsitagliptin, alpha glucosidase inhibitor such as acarbose, anti-diabeticcombination such as ActoPlusMet, AvandaMet, metformin/pioglitazone,metformin/rosiglitazone, or Glucovance, Glucagon-like peptide-1 analoguesuch as exenatide or liraglutide, Amylin analogue such as pramlintide,statin such as atorvastatin, simvastatin, rosuvastatin, pravastatin,fluvastatin, lovastatin, or pitavastatin, Cholesterol absorptioninhibitor such as ezetimibe, Nicotinic acid derivative such as niacin orniaslo, antidyslipidemic fixed combination such assimvastatin/ezetimibe, lovastatin/nicotinic acid,atorvastatin/amlodipine, or atorvastatin/torcetrapib,simvastatin/nicotinic acid, ACE inhibitor such as ramipril, captopril,or lisinopril, AT-II receptor antagonist such as valsartan ortelmisartan, cannabinoid receptor antagonist such as rimonabant,cholesteryl ester transfer protein or CETP Inhibitor such as JTT-705,CETi-1, or beta-3 adrenergic agonist.

In one embodiment, the compound is administered with an agent treating awasting disease. In some embodiments, agents treating a wasting diseaseinclude but are not limited to corticosteroids, anabolic steroids,cannabinoids, metoclopramid, cisapride, medroxyprogesterone acetate,megestrol acetate, cyproheptadine, hydrazine sulfate, pentoxifylline,thalidomide, anticytokine antibodies, cytokine inhibitors,eicosapentaenoic acid, indomethacin, ibuprofen, melatonin, insulin,growth hormone, clenbuterol, porcine pancreas extract, IGF-1, IGF-1analogue and secretagogue, myostatin analogue, proteasome inhibitor,testosterone, oxandrolone, enbrel, melanocortin 4 receptor agonist, or acombination thereof.

In one embodiment, the agent treating a wasting disease is a ghrelinreceptor ligand, growth hormone analogue, or a secretagogue. In someembodiments, ghrelin receptor ligands, growth hormone analogues, orsecretagogues include but are not limited to pralmorelin, examorelin,tabimorelin, capimorelin, capromorelin, ipamorelin, EP-01572, EP-1572,or JMV-1843.

In one embodiment, growth promoting agents such as but not limited toTRH, diethylstilbesterol, theophylline, enkephalins, E seriesprostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345, e.g.,zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979, e.g.,sulbenox or peptides disclosed in U.S. Pat. No. 4,411,890 are utilizedas agents treating a wasting disease.

In other embodiments, agents treating a wasting disease may comprisegrowth hormone secretagogues such as GHRP-6, GHRP-1 (as described inU.S. Pat. No. 4,411,890 and publications WO 89/07110 and WO 89/07111),GHRP-2 (as described in WO 93/04081), NN703 (Novo Nordisk), LY444711(Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, or, in otherembodiments, with growth hormone releasing factor and its analogs orgrowth hormone and its analogs, or with alpha-adrenergic agonists, suchas clonidine or serotinin 5-HTD agonists, such as sumatriptan, or agentswhich inhibit somatostatin or its release, such as physostigmine andpyridostigmine. In some embodiments, agents treating a wasting diseasemay comprise parathyroid hormone, PTH (1-34) or bisphosphonates, such asMK-217 (alendronate). In other embodiments, agents treating wastingdisease may further comprise estrogen, a selective estrogen receptormodulator, such as tamoxifene or raloxifene, or other androgen receptormodulators, such as those disclosed in Edwards, J. P. et. al., Bio. Med.Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et. al., J. Med.Chem., 42, 210-212 (1999). In some embodiments, agents treating awasting disease may further comprise a progesterone receptor agonists(“PRA”), such as levonorgestrel, medroxyprogesterone acetate (MPA). Insome embodiments, agents treating a wasting disease may includenutritional supplements, such as those described in U.S. Pat. No.5,179,080, which, in other embodiments are in combination with wheyprotein or casein, amino acids (such as leucine, branched amino acidsand hydroxymethylbutyrate), triglycerides, vitamins (e.g., A, B6, B 12,folate, C, D and E), minerals (e.g., selenium, magnesium, zinc,chromium, calcium and potassium), camitine, lipoic acid, creatinine,B-hyroxy-B-methylbutyriate (Juven) and coenzyme Q. In one embodiment,agents treating a wasting disease may further comprise antiresorptiveagents, vitamin D analogues, elemental calcium and calcium supplements,cathepsin K inhibitors, MMP inhibitors, vitronectin receptorantagonists, Src SH2 antagonists, vacular-H+-ATPase inhibitors,ipriflavone, fluoride, fibolone, prostanoids, 17-beta hydroxysteroiddehydrogenase inhibitors and Src kinase inhibitors.

In one embodiment, the compound is administered in with an agenttreating the endocrine system. In some embodiments, agents treating theendocrine system include but are not limited to radioactive iodine,antithyroid agent, thyroid hormone supplement, growth hormone,cabergoline, bromocriptine, thyroxine, gonadotropin, glucocorticoid,glucocorticoid analogue, corticotrophin, metyrapone, aminoglutethimide,mitotane, ketoconazole, mifepristone, dexamethasone somatostatinanalogue, gonadotropin-releasing hormone analogue, leuprolide,goserelin, antidiuretic hormone, antidiuretic hormone analogue,oxytocin, calcium supplement, vitamin D, or a combination thereof.

In one embodiment, the agent treating the endocrine system is a5-alpha-reductase inhibitor. In some embodiments, 5-alpha-reductaseinhibitors include but are not limited to finasteride, dutasteride, orizonsteride.

In one embodiment, the agent treating the endocrine system is a SARMcompound. In some embodiments, SARMs include but are not limited toRU-58642, RU-56279, WS9761 A and B, RU-59063, RU-58841, bexlosteride,LG-2293, L-245976, LG-121071, LG-121091, LG-121104, LGD-2226, LGD-2941,YM-92088, YM-175735, LGD-1331, BMS-357597, BMS-391197, S-40503,BMS-482-404, EM-4283, EM-4977, BMS-564929, BMS-391197, BMS-434588,BMS-487745, BMS-501949, SA-766, YM-92088, YM-580, LG-123303, LG-123129,PMCol, YM-175735, BMS-591305, BMS-591309, BMS-665139, BMS-665539,CE-590, 116BG33, 154BG31, arcarine, or ACP-105.

In one embodiment, the additional agent treating the endocrine system isa SERM compound. In some embodiments, SERMs include but are not limitedto tamoxifene, 4-hydroxytamoxifene, idoxifene, toremifene, ospemifene,droloxifene, raloxifene, arzoxifene, bazedoxifene, PPT(1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole), DPN, lasofoxifene,pipendoxifene, EM-800, EM-652, nafoxidine, zindoxifene, tesmilifene,miproxifene phosphate, RU 58,688, EM 139, ICI 164,384, ICI 182,780,clomiphene, MER-25, diethylstibestrol, coumestrol, genistein, GW5638,LY353581, zuclomiphene, enclomiphene, delmadinone acetate, DPPE,(N,N-diethyl-2-{4-(phenylmethyl)-phenoxy}ethanamine), TSE-424, WAY-070,WAY-292, WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, WAY-244,ERB-196, WAY-169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, BE-380,BE-381, WAY-358, [18F]FEDNP, LSN-500307, AA-102, Ban zhi lian, CT-10,CT-102, or VG-101.

In one embodiment, the agent treating the endocrine system is agonadotropin-releasing hormone agonist or antagonist. In someembodiments, gonadotropin-releasing hormone agonists or antagonistsinclude but are not limited to leuprolide, goserelin, triptorelin,alfaprostol, histrelin, detirelix, ganirelix, antide iturelix,cetrorelix, ramorelix, ganirelix, antarelix, teverelix, abarelix,ozarelix, sufugolix, prazarelix, degarelix, NBI-56418, TAK-810, oracyline.

In one embodiment, the agent treating the endocrine system is aluteinizing hormone agonist or antagonist. In some embodiments,luteinizing hormone agonists or antagonists include but are not limitedto letrozole, anastrazole, atamestane, fadrozole, minamestane,exemestane, plomestane, liarozole, NKS-01, vorozole, YM-511, finrozole,4-hydroxyandrostenedione, aminogluethimide, or rogletimide. In oneembodiment, the agent treating the endocrine system is a folliclestimulating hormone agonist or antagonist. In one embodiment, the agenttreating the endocrine system is a luteinizing hormone releasing hormone(LHRH) or a LHRH analog.

In one embodiment, the agent treating the endocrine system is asteroidal or nonsteroidal glucocorticoid receptor ligand. In someembodiments, nonsteroidal glucocorticoid receptor ligands include butare not limited to ZK-216348, ZK-243149, ZK-243185, LGD-5552,mifepristone, RPR-106541, ORG-34517, GW-215864×, Sesquicillin,CP-472555, CP-394531, A-222977, AL-438, A-216054, A-276575, CP-394531,CP-409069, or UGR-07.

In one embodiment, the agent treating the endocrine system is asteroidal or non-steroidal progesterone receptor ligand. In oneembodiment, the agent treating the endocrine system is a steroidal ornonsteroidal androgen receptor antagonist. In some embodiments,steroidal or nonsteroidal androgen receptor antagonists include but arenot limited to flutamide, hydroxyflutamide, bicalutamide, nilutamide, orhydroxysteroid dehydrogenase inhibitor.

In one embodiment, the agent treating the endocrine system is aperoxisome proliferator-activated receptor ligand. In some embodiments,peroxisome proliferator-activated receptor ligands include but are notlimited to bezafibrate, fenofibrate, gemfibrozil, darglitazone,pioglitazone, rosiglitazone, isaglitazone, rivoglitazone, netoglitazone,naveglitazar, farglitazar, tesaglitazar, ragaglitazar, oxeglitazar, orPN-2034.

In one embodiment, an agent treating the endocrine system is a humangrowth hormone. In some embodiments, human growth hormones include butare not limited to somatotropin or analogues.

In one embodiment, the agent treating the endocrine system is a ghrelin.In some embodiments, ghrelins include but are not limited to humanghrelin, CYT-009-GhrQb, L-692429, GHRP-6, SK&F-110679, or U-75799E.

In one embodiment, the agent treating the endocrine system is a leptin.In some embodiments, leptins include but are not limited to metreleptinor pegylated leptin. In one embodiment, an agent treating the endocrinesystem is a leptin receptor agonist. In some embodiments, leptinreceptor agonists include but are not limited to LEP (116-130), OB3,[D-Leu4]-OB3, rAAV-leptin, AAV-hOB, or rAAVhOB.

In one embodiment, the SARM compound is administered with an inhibitorof an enzyme involved in the androgen biosynthetic pathway. In someembodiments, inhibitors of enzymes involved in the androgen biosyntheticpathway include but are not limited to 17-ketoreductase inhibitor,3-DH4,6-isomerase inhibitor, 3-DH4,5-isomerase inhibitor, 17,20desmolase inhibitor, p450c17 inhibitor, p450ssc inhibitor, or17,20-lyase inhibitor.

In one embodiment, the SARM compound is administered with an agenttreating osteoporosis. In some embodiments, osteoporosis is induced byalcohol and/or smoking. In some embodiments, agents treatingosteoporosis include but are not limited to SERMs, calcitonin, vitaminD, vitamin D derivatives, vitamin D receptor ligand, vitamin D receptorligand analogue, estrogen, estrogen derivative, conjugated estrogen,antiestrogen, progestin, synthetic estrogen, synthetic progestin, RANKligand monoclonal antibody, integrin receptor antagonist, osteoclastvacuolar ATPase inhibitor, antagonist of VEGF binding to osteoclastreceptors, calcium receptor antagonist, parathyroid hormone, parathyroidhormone analogue, parathyroid hormone-related peptide, cathepsin Kinhibitor, strontium ranelate, tibolone, HCT-1026, PSK3471, galliummaltolate, nutropin AQ, prostaglandin, p38 protein kinase inhibitor,bone morphogenetic protein (BMP), inhibitor of BMP antagonism, HMG-CoAreductase inhibitor, vitamin K, vitamin K derivative, ipriflavone,fluoride salts, dietary calcium supplement, or osteoprotegerin.

In one embodiment, the agent treating osteoporosis is a calcitonin. Insome embodiments, calcitonins include but are not limited to salmon,elcatonin, SUN-8577, or TJN-135.

In one embodiment, the agent treating osteoporosis is a vitamin Dreceptor ligand or analogue. In some embodiments, vitamin D receptorligands or analogues include but are not limited to calcitriol,topitriol, ZK-150123, TEI-9647, BXL-628, Ro-26-9228, BAL-2299,Ro-65-2299, or DP-035.

In one embodiment, the SARM compound is administered with an agenttreating pharmacotherapy induced hypogonadal and/or osteopenic and/orsarcopenic state. In some embodiments, agents treating pharmacotherapyinduced hypogonadal and/or osteopenic and/or sarcopenic states includebut are not limited to opioids, narcotics, opiates, opioids, methadone,kadian, D2 dopamine receptor antagonist, zotepine, haloperidol,amisulpride, risperidone, anti-epileptic agent, valproic acid,carbamazepine, oxcarbamazepine, chemotherapeutic agent, methotrexate,cyclophosphamide, ifosfamide, adriamycin, doxorubicin, glucocorticoids,cyclosporine, L-thyroxine, SERMs, AI, fulvestrant,gonadotropin-releasing hormone agent, androgen depravation agent,prolactinemia-inducing agent, serotonergic antidepressant, selectiveserotonin reuptake inhibitor, monoamine oxidase inhibitor, tricyclicantidepressant, antihypertensive agents, methyldopa, reserpine,clonidine, verapamil, antidopaminergic agent, anti-emetic agent,metoclopramide, H2 receptor antagonist, cimetidine, ranitidine,estrogen, or amphetamine.

In one embodiment, the compound of this invention is administered with avitamin. In some embodiments, vitamins include but are not limited tovitamin D, vitamin E, vitamin K, vitamin B, vitamin C, or a combinationthereof.

In one embodiment, the compound of this invention is administered with abehavior-modulating agent. In some embodiments, behavior-modulatingagents include but are not limited to an anti-anxiety agent,anti-psychotic agent, anti-depressant, beta-blocker, beta-2 agonist,anticholinergic bronchodilator, theophylline, aminophylline, nedocromilsodium, sodium cromoglycate, leukotriene receptor antagonist,corticosteroid, expectorant, mucolytic agent, antihistamine,pseudoephedrine, methylphenidate, amphetamine, buspirone,benzodiazepine, dextroamphetamine, tricyclic antidepressant, serotoninreuptake inhibitor, phenothiazines, benztropine, bupropion, propranolol,lithium, venlafaxine, haloperidol, buspirone, or a neuraminidaseinhibitor.

In one embodiment, the behavior-modulating agent is a benzodiazepine. Inone embodiment, benzodiazepines comprise alprazolam, chlordiazepoxide,diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam.

In one embodiment, the behavior-modulating agent is a phenothiazine. Inone embodiment, phenothiazines comprise fluphenazine, perphenazine,thioridazine, or trifluoperazine.

In one embodiment, the behavior-modulating agent is a tricyclicantidepressant or a serotonin reuptake inhibitor. In one embodiment,tricyclic antidepressants or serotonin reuptake inhibitors comprisephenothiazine, protriptyline, fluoxetine, paroxetine, or sertraline.

In one embodiment, the compound of this invention is administered withan agent treating a connective tissue. In some embodiments, agentstreating a connective tissue include but are not limited to ananti-malaria agent, a cytotoxic agent, a steroid, corticosteroid, lupusmedication, imuran, cytoxan, anti-rheumatic agent, corticosteroid,nifedipine, aspirin, coichicine, captopril, penicillamine, azathioprine,methotrexate, cyclophosphamide, prednisone, nicardipine, or anon-steroidal anti-inflammatory agent.

In one embodiment, the compound of this invention is administered withan agent treating an ophthalmic disease. In some embodiments, agentstreating an ophthalmic disease include but are not limited to betagan,betimol, timoptic, betoptic, betoptic, ocupress, optipranolol, xalatan,alphagan, azopt, trusopt, cospot, pilocar, pilagan, propine, opticrom,acular, livostin, alomide, emadine, patanol, alrex, poly-pred, pred-g,dexacidin, erythromycin, maxitrol, tobradex, blephamide, FML, ocufen,voltaren, profenal, pred forte, econpred plus, eflone, flarex, inflamaseforte, betadine, gramicidin, prednisolone, betaxolol, humorsol,proparacaine, betoptic, hylartin, inflamase mild, lotemax, flurbiprofen,chloramphenicol, methazolamide, timolol, ciloxan, terramycin,ciprofloxacin, miostat, triamcinolone, miconazole, tobramycin,physostimine, gentamicin, pilocarpine, bacitracin, goniosol, polymyxin,oxytetracycline, viroptic, vexol, suprofen, celluvisc, polytrim,illotycin, ciloxan, ocuflox, brinzolamide, cefazolin, tobrex,latanoprost, indocycanine, trifluridine, phenylephrine, demecarium,neomycin, tropicamide, dexamethasone, neptazane, dipivefrin, ocuflox,vidarabine, dorzolamide, ofloxacin, epinephrine, acyclovir, carbonicanhydrase inhibitor, antihistamine vitamin A, vitamin C, vitamin E,zinc, copper, atropine, or garamycin.

In one embodiment, the compound of this invention is administered inwith a gene therapy agent. In some embodiments, gene therapy agentsinclude but are not limited to an antisense agent, or a replacementgene.

In some embodiments, any of the compositions of this invention willcomprise a compound of formula I, in any form or embodiment as describedherein. In some embodiments, any of the compositions of this inventionwill consist of a compound of formula I, in any form or embodiment asdescribed herein. In some embodiments, of the compositions of thisinvention will consist essentially of a compound of I, in any form orembodiment as described herein. In some embodiments, the term “comprise”refers to the inclusion of the indicated active agent, such as thecompound of formula I, as well as inclusion of other active agents, andpharmaceutically acceptable carriers, excipients, emollients,stabilizers, etc., as are known in the pharmaceutical industry. In someembodiments, the term “consisting essentially of” refers to acomposition, whose only active ingredient is the indicated activeingredient, however, other compounds may be included which are forstabilizing, preserving, etc. the formulation, but are not involveddirectly in the therapeutic effect of the indicated active ingredient.In some embodiments, the term “consisting essentially of” may refer tocomponents which facilitate the release of the active ingredient. Insome embodiments, the term “consisting” refers to a composition, whichcontains the active ingredient and a pharmaceutically acceptable carrieror excipient.

In one embodiment, the present invention provides combined preparations.In one embodiment, the term “a combined preparation” defines especiallya “kit of parts” in the sense that the combination partners as definedabove can be dosed independently or by use of different fixedcombinations with distinguished amounts of the combination partnersi.e., simultaneously, concurrently, separately or sequentially. In someembodiments, the parts of the kit of parts can then, e.g., beadministered simultaneously or chronologically staggered, that is atdifferent time points and with equal or different time intervals for anypart of the kit of parts. The ratio of the total amounts of thecombination partners, in some embodiments, can be administered in thecombined preparation. In one embodiment, the combined preparation can bevaried, e.g., in order to cope with the needs of a patient subpopulationto be treated or the needs of the single patient which different needscan be due to a particular disease, severity of a disease, age, sex, orbody weight as can be readily made by a person skilled in the art.

It is to be understood that this invention is directed to compositionsand combined therapies as described herein, for any disease, disorder orcondition, as appropriate, as will be appreciated by one skilled in theart. Certain applications of such compositions and combined therapieshave been described hereinabove, for specific diseases, disorders andconditions, representing embodiments of this invention, and methods oftreating such diseases, disorders and conditions in a subject byadministering a compound as herein described, alone or as part of thecombined therapy or using the compositions of this invention representadditional embodiments of this invention.

Biological Activity of Selective Androgen Modulator Compounds

The compounds of this invention may be useful, in some embodiments, fororal testosterone replacement therapy. In other embodiments,appropriately substituted compounds are useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with ADAM, such as fatigue,depression, decreased libido, sexual dysfunction, erectile dysfunction,hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia,benign prostate hyperplasia, and alterations in mood and cognition; c)treatment of conditions associated with ADIF, such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of chronic muscularwasting; e) treatment of prostate cancer, imaging of prostate cancer;decreasing the incidence of, halting or causing a regression of prostatecancer; f) treatment of diabetes type I; g) treatment of diabetes typeII; h) suppressing or inhibiting or reducing the incidence of diabetesi) treatment of glucose intolerance; j) treatment of hyperinsulinemia;k) treatment of insulin resistance 1) treatment of diabetic nephropathy;m) treatment of diabetic neuropathy; n) treatment of diabeticretinopathy; o) treatment of fatty liver condition; p) treatment ofcachexia; q) oral androgen replacement and/or other clinical therapeuticand/or diagnostic areas, including any embodiment of what is encompassedby the term “treating” as described herein.

In some embodiments, the compounds of this invention possess in vivotissue selective androgenic and anabolic activity, which is accordinglyutilized for particular applications, as will be appreciated by oneskilled in the art.

In one embodiment, this invention provides: a) a method of treating asubject having a muscle wasting disorder; b) a method of treating asubject suffering from malnutrition; c) a method of treating abone-related disorder in a subject; d) a method of increasing a bonemass in a subject; e) a method of improving the lipid profile in asubject; f) a method of treating atherosclerosis and its associateddiseases; g) a method of improving dexterity and movement in a subject;h) a method of treating a subject having dwarfism; i) a method oftreating a subject having dysmenorrhea; j) a method of treating asubject having dysparunia; k) a method of treating a subject havingdysspermtogenic sterility; comprising the step of administering to saidsubject a compound of this invention and/or an analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, prodrug, polymorph, impurity or crystal ofsaid compound, or any combination thereof. In one embodiment, thecompound may be characterized by the structure of formula I-XXII, or anyembodiment thereof, as herein described.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications andtreating diseases in which the improvement of cognition, reduction ortreatment of depression, or other neuroportective effects are desired.

In one embodiment, “Cognition” refers to the process of knowing,specifically the process of being aware, knowing, thinking, learning andjudging. Cognition is related to the fields of psychology, linguistics,computer science, neuroscience, mathematics, ethology and philosophy. Inone embodiment, “mood” refers to a temper or state of the mind. Ascontemplated herein, alterations mean any change for the positive ornegative, in cognition and/or mood.

In one embodiment, “depression” refers to an illness that involves thebody, mood and thoughts that affects the way a person eats, sleeps andthe way one feels about oneself, and thinks about things. The signs andsymptoms of depression include loss of interest in activities, loss ofappetite or overeating, loss of emotional expression, an empty mood,feelings of hopelessness, pessimism, guilt or helplessness, socialwithdrawal, fatigue, sleep disturbances, trouble concentrating,remembering, or making decisions, restlessness, irritability, headaches,digestive disorders or chronic pain.

In one embodiment, the methods of this invention are useful a subject,which is a human. In another embodiment, the subject is a mammal. Inanother embodiment the subject is an animal. In another embodiment thesubject is an invertebrate. In another embodiment the subject is avertebrate.

In one embodiment, the subject is male. In another embodiment, thesubject is female. In some embodiments, while the methods as describedherein may be useful for treating either males or females, females mayrespond more advantageously to administration of certain compounds, forcertain methods, as described and exemplified herein.

In some embodiments, while the methods as described herein may be usefulfor treating either males or females, males may respond moreadvantageously to administration of certain compounds, for certainmethods, as described herein.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications in ortreating hair loss, alopecia, androgenic alopecia, alopecia areata,alopecia secondary to chemotherapy, alopecia secondary to radiationtherapy, alopecia induced by scarring or alopecia induced by stress. Inone embodiment, “hair loss”, or “alopecia”, refers to baldness as in thevery common type of male-pattern baldness. Baldness typically beginswith patch hair loss on the scalp and sometimes progresses to completebaldness and even loss of body hair. Hair loss affects both males andfemales.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications in, ortreating diseases or conditions associated with a subject having anemia.In one embodiment, “anemia” refers to the condition of having less thanthe normal number of red blood cells or less than the normal quantity ofhemoglobin in the blood, reduced hematocrit or reduced mean corpuscularvolume, or reduced corpuscular size. The oxygen-carrying capacity of theblood is decreased in anemia. In some embodiments, treating anemia mayalso refer herein to treating underlying factors resulting in anemia,such as for example: a) hemorrhage (bleeding); b) hemolysis (excessivedestruction of red blood cells); c) underproduction of red blood cells;and d) not enough normal hemoglobin. In some embodiments, treatinganemia in this invention refers to treating any form thereof, includingaplastic anemia, benzene poisoning, Fanconi anemia, hemolytic disease ofthe newborn, hereditary spherocytosis, iron deficiency anemia,osteoporosis, pernicious anemia, aplastic anemia, hemolytic anemia,sickle cell anemia, renal anemia, thalassemia, myelodysplastic syndrome,and a variety of bone marrow diseases.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications in and/ortreating diseases and/or conditions associated with problems with asubject's libido, or erectile dysfunction in a subject. In oneembodiment, “libido”, may refer to sexual desire.

In one embodiment, the term “erectile” refers to the ability to be erector upright. An erectile tissue is a tissue, which is capable of beinggreatly dilated and made rigid by the distension of the numerous bloodvessels, which it contains.

In another embodiment of the present invention, a method is provided forhormonal therapy in a patient (i.e., one suffering from anandrogen-dependent condition) which includes contacting an androgenreceptor of a patient with a compound and/or a non steroidal agonist ofthe present invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, hydrate, N-oxide or any combination thereof, in anamount effective to bind the compound to the androgen receptor andeffect a change in an androgen-dependent condition.

In one embodiment of this invention, a method is provided for hormonereplacement therapy in a patient (i.e., one suffering from anandrogen-dependent condition) which includes administering a compound asherein described and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, hydrate, N-oxide or any combination thereof, to asubject, in an amount sufficient to effect a change in ahormone-dependent condition in the subject.

Androgen-dependent conditions which may be treated with the compoundsand/or compositions as herein described, comprising the methods of thepresent invention include those conditions which are associated withaging, hypogonadism, sarcopenia, diminished erythropoiesis,osteoporosis, and any other conditions dependent upon low androgen(e.g., testosterone) or estrogen levels.

Androgen-dependent conditions which may be treated with the compoundsand/or compositions as herein described, and comprising a method of theinvention, may comprise conditions characterized by elevated androgen orestrogen levels, including hirsutism, infertility, polycystic ovariansyndrome, endometrial carcinoma, breast cancer, male pattern baldness,prostate cancer, testicular cancer, and others, as will be known to oneskilled in the art. For such conditions, the subject may be administereda compound as herein described, alone or in combination with anothertherapeutic agent, as will be appreciated by one skilled in the art.

In one embodiment, this invention provides methods for the treatment ofa cancer in a subject, reduction of incidence or severity orpathogenesis of a cancer in a subject, delaying progression, prolongingremission or delaying onset of cancer in a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, hydrate,N-oxide or any combination thereof. In some embodiments, such cancersare hormone-dependent or androgen receptor dependent tumors (malignantor benign) associated with reproductive tissue in males or females, suchas cancer of the prostate, ovary, breast, uterus, testicle, or others.

In some embodiments, this invention provides methods for the treatmentof a precancerous precursor or lesion in a subject, reduction ofincidence of precancerous precursors or lesions in a subject, comprisingthe step of administering to the subject a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,hydrate, N-oxide or any combination thereof. In some embodiments, suchprecancerous precursors are androgen receptor dependent tumors found inhormone-responsive tissue or are associated with reproductive tissue inmales or females, such as in the prostate, ovary, breast, uterus,testicle, or others. In some embodiments, such precancerous precursorscomprise any local intraepithelial neoplasia, for example, of theprostate, the cervix, etc. In some embodiments, such methods are usefulin treating neoplasia or pre-neoplasia, dysplasia or hyperplasia in atissue, such as in reproductive tissue in males or females.

In one embodiment, this invention provides compounds, compositionsand/or methods of use thereof in treating benign prostate hyperplasia(BPH). “BPH (benign prostate hyperplasia)” is a nonmalignant enlargementof the prostate gland, and is the most common non-malignantproliferative abnormality found in any internal organ and the majorcause of morbidity in the adult male. BPH occurs in over 75% of men over50 years of age, reaching 88% prevalence by the ninth decade. BPHfrequently results in a gradual squeezing of the portion of the urethrawhich traverses the prostate (prostatic urethra). This causes patientsto experience a frequent urge to urinate because of incomplete emptyingof the bladder and urgency of urination. The obstruction of urinary flowcan also lead to a general lack of control over urination, includingdifficulty initiating urination when desired, as well as difficulty inpreventing urinary flow because of the inability to empty urine from thebladder, a condition known as overflow urinary incontinence, which canlead to urinary obstruction and to urinary failure.

In another embodiment of the present invention, the method for treatingbenign prostate hyperplasia (BPH) in a subject, comprises the step ofadministering to the subject a compound as herein described and/or itsanalog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, hydrate,N-oxide or any combination thereof, in an amount effective to treat BPHin the subject.

In some embodiments, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, or reducing pathogenesis of cachexia and/or cachexia associated withcancer in a subject. In another embodiment, the cancer compriseadrenocortical carcinoma, anal cancer, bladder cancer, brain tumor,brain stem glioma, brain tumor, cerebellar astrocytoma, cerebralastrocytoma, ependymoma, medulloblastoma, supratentorial primitiveneuroectodermal, pineal tumors, hypothalamic glioma, breast cancer,carcinoid tumor, carcinoma, cervical cancer, colon cancer, endometrialcancer, esophageal cancer, extrahepatic bile duct cancer, ewings familyof tumors (Pnet), extracranial germ cell tumor, eye cancer, intraocularmelanoma, gallbladder cancer, gastric cancer, germ cell tumor,extragonadal, gestational trophoblastic tumor, head and neck cancer,hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer, leukemia,acute lymphoblastic, leukemia, oral cavity cancer, liver cancer, lungcancer, non small cell lung cancer, small cell, lymphoma, AIDS-relatedlymphoma, central nervous system (primary), lymphoma, cutaneous T-cell,lymphoma, Hodgkin's disease, non-Hodgkin's disease, malignantmesothelioma, melanoma, Merkel cell carcinoma, metasatic squamouscarcinoma, multiple myeloma, plasma cell neoplasms, mycosis fungoides,myelodysplastic syndrome, myeloproliferative disorders, nasopharyngealcancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarianepithelial cancer, ovarian germ cell tumor, ovarian low malignantpotential tumor, pancreatic cancer, exocrine, pancreatic cancer, isletcell carcinoma, paranasal sinus and nasal cavity cancer, parathyroidcancer, penile cancer, pheochromocytoma cancer, pituitary cancer, plasmacell neoplasm, prostate cancer, rhabdomyosarcoma, rectal cancer, renalcell cancer, salivary gland cancer, Sezary syndrome, skin cancer,cutaneous T-cell lymphoma, skin cancer, Kaposi's sarcoma, skin cancer,melanoma, small intestine cancer, soft tissue sarcoma, soft tissuesarcoma, testicular cancer, thymoma, malignant, thyroid cancer, urethralcancer, uterine cancer, sarcoma, unusual cancer of childhood, vaginalcancer, vulvar cancer, Wilms' tumor, or any combination thereof.

In another embodiment, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, delaying the onset of lung cancer.

In another embodiment, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, delaying the onset of non small cell lung cancer.

In some embodiments, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, or reducing pathogenesis of cancer. In another embodiment, thecancer comprises androgen AR dependent tumors (malignant or benign) suchas prostate cancer, breast cancer (male or female, operable orinoperable). In another embodiment the SARM compounds adjunct to ADT fortreating prostate cancer; bladder cancers; brain cancers; bone tumors,colon cancer, endometrial cancer, liver cancer, lung cancer, lymphaticcancer, kidney cancer, osteosarcoma cancer, ovarian cancer, pancreascancer, penis cancer, skin cancer, thyroid cancer; and/orhormone-dependent cancers.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for a) treating a bone related disorder; b) preventing a bonerelated disorder; c) suppressing a bone related disorder; d) inhibitinga bone related disorder; e) increasing a strength of a bone of asubject; f) increasing a bone mass in a subject; g) use forosteoclastogenesis inhibition.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for a) Accelerate bone repair; b) treating bone disorders; c)treating bone density loss; d) treating low bone mineral density (BMD);e) treating reduced bone mass; f) treating metabolic bone disease; g)promoting bone growth or regrowth; h) promoting bone restoration; i)promoting bone fracture repair; j) promoting bone remodeling; k)treating bone damage following reconstructive surgery including of theface, hip, or joints; 1) enhancing of bone strength and function; m)increasing cortical bone mass; n) increasing trabecular connectivity.

In one embodiment, the bone related disorder is a genetic disorder, orin another embodiment, is induced as a result of a treatment regimen fora given disease. For example, and in one embodiment, the compounds asherein described are useful in treating a bone-related disorder thatarises as a result of cancer metastasis to bone, or in anotherembodiment, as a result of androgen-deprivation therapy, for example,given in response to prostate carcinogenesis in the subject.

In one embodiment, the bone-related disorder is osteoporosis. In anotherembodiment, the bone-related disorder is osteopenia. In anotherembodiment, the bone-related disorder is increased bone resorption. Inanother embodiment, the bone-related disorder is bone fracture. Inanother embodiment, the bone-related disorder is bone frailty.

In another embodiment, the bone-related disorder is a loss of bonemineral density (BMD). In another embodiment, the bone-related disorderis any combination of osteoporosis, osteopenia, increased boneresorption, bone fracture, bone frailty and loss of BMD. Each disorderrepresents a separate embodiment of the present invention.

“Osteoporosis” refers, in one embodiment, to a thinning of the boneswith reduction in bone mass due to depletion of calcium and boneprotein. In another embodiment, osteoporosis is a systemic skeletaldisease, characterized by low bone mass and deterioration of bonetissue, with a consequent increase in bone fragility and susceptibilityto fracture. In osteoporotic patients, bone strength is abnormal, in oneembodiment, with a resulting increase in the risk of fracture. Inanother embodiment, osteoporosis depletes both the calcium and theprotein collagen normally found in the bone, in one embodiment,resulting in either abnormal bone quality or decreased bone density. Inanother embodiment, bones that are affected by osteoporosis can fracturewith only a minor fall or injury that normally would not cause a bonefracture. The fracture can be, in one embodiment, either in the form ofcracking (as in a hip fracture) or collapsing (as in a compressionfracture of the spine). The spine, hips, and wrists are common areas ofosteoporosis-induced bone fractures, although fractures can also occurin other skeletal areas. Unchecked osteoporosis can lead, in anotherembodiment, to changes in posture, physical abnormality, and decreasedmobility.

In one embodiment, the osteoporosis results from androgen deprivation.In another embodiment, the osteoporosis follows androgen deprivation. Inanother embodiment, the osteoporosis is primary osteoporosis. In anotherembodiment, the osteoporosis is secondary osteoporosis. In anotherembodiment, the osteoporosis is postmenopausal osteoporosis. In anotherembodiment, the osteoporosis is juvenile osteoporosis. In anotherembodiment, the osteoporosis is idiopathic osteoporosis. In anotherembodiment, the osteoporosis is senile osteoporosis.

In another embodiment, the primary osteoporosis is Type I primaryosteoporosis. In another embodiment, the primary osteoporosis is Type IIprimary osteoporosis. Each type of osteoporosis represents a separateembodiment of the present invention.

According to this aspect of the invention and in one embodiment, thebone-related disorder is treated with a compound as herein described, ora combination thereof. In another embodiment, other bone-stimulatingcompounds can be provided to the subject, prior to, concurrent with orfollowing administration of a compound or compounds as herein described.In one embodiment, such a bone stimulating compound may comprise naturalor synthetic materials.

In one embodiment, the bone stimulating compound may comprise a bonemorphogenetic protein (BMP), a growth factor, such as epidermal growthfactor (EGF), a fibroblast growth factor (FGF), a transforming growthfactor (TGF, an insulin growth factor (IGF), a platelet-derived growthfactor (PDGF) hedgehog proteins such as sonic, indian and deserthedgehog, a hormone such as follicle stimulating hormone, parathyroidhormone, parathyroid hormone related peptide, activins, inhibins,follistatin, frizzled, frzb or frazzled proteins, BMP binding proteinssuch as chordin and fetuin, a cytokine such as IL-3, IL-7, GM-CSF, achemokine, such as eotaxin, a collagen, osteocalcin, osteonectin andothers, as will be appreciated by one skilled in the art.

In another embodiment, the compositions for use in treating a bonedisorder of this invention may comprise a compound or compounds asherein described, an additional bone stimulating compound, or compounds,and osteogenic cells. In one embodiment, an osteogenic cell may be astem cell or progenitor cell, which may be induced to differentiate intoan osteoblast. In another embodiment, the cell may be an osteoblast. Inanother embodiment, nucleic acids which encode bone-stimulatingcompounds may be administered to the subject, which is to be consideredas part of this invention.

In one embodiment, the methods of the present invention compriseadministering the compound for treating osteoporosis. In anotherembodiment, the methods of this invention comprise administering acompound in combination with SERMs for treating osteoporosis. In anotherembodiment, the SERMs are tamoxifene, 4-hydroxytamoxifene, idoxifene,toremifene, ospemifene, droloxifene, raloxifene, arzoxifene,bazedoxifene, PPT (1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole),DPN, lasofoxifene, pipendoxifene, EM-800, EM-652, nafoxidine,zindoxifene, tesmilifene, miproxifene phosphate, RU 58,688, EM 139, ICI164,384, ICI 182,780, clomiphene, MER-25, diethylstibestrol, coumestrol,genistein, GW5638, LY353581, zuclomiphene, enclomiphene, delmadinoneacetate, DPPE, (N,N-diethyl-2-[4-(phenylmethyl)-phenoxy]ethanamine),TSE-424, WAY-070, WAY-292, WAY-818, cyclocommunol, prinaberel, ERB-041,WAY-397, WAY-244, ERB-196, WAY-169122, MF-101, ERb-002, ERB-037,ERB-017, BE-1060, BE-380, BE-381, WAY-358, [18F]FEDNP, LSN-500307,AA-102, Ban zhi lian, CT-101, CT-102, or VG-101.

In another embodiment, the methods of the present invention compriseadministering the SARM compound, in combination with bisphosphonatessuch as alendronate, tiludroate, clodroniate, pamidronate, etidronate,alendronate, zolendronate, cimadronate, neridronate, minodronic acid,ibandronate, risedronate, or homoresidronate for treating osteoporosis.

In another embodiment, the methods of the present invention compriseadministering the compound, in combination with Calcitonin such assalmon, Elcatonin, SUN-8577 or TJN-135 for treating osteoporosis.

In another embodiment, the methods of treating osteoporosis of thepresent invention comprise administering the SARM compound, incombination with a) vitamin D or derivative such as ZK-156979; b)vitamin D receptor ligand and analogues such as calcitriol, topitriol,ZK-150123, TEI-9647, BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299 orDP-035; c) estrogen, estrogen derivative, or conjugated estrogens; d)antiestrogen, progestins, or synthetic estrogen/progestins; e) RANKligand mAb such as denosumab formerly AMG162 (Amgen); f) ανβ3 Integrinreceptor antagonist; g) osteoclast vacuolar ATPase inhibitor; h)antagonist of VEGF binding to osteoclast receptors; i) calcium receptorantagonist; j) PTh (parathyroid hormone) and analogues, PTHrP analogues(parathyroid hormone-related peptide); k) Cathepsin K inhibitors (ME581,etc.); 1) strontium ranelate; m) tibolone; n) HCT-1026, PSK3471; o)gallium maltolate; p) nutropin AQ; q) prostaglandins (for osteo); r) p38protein kinase inhibitor; s) bone morphogenetic protein; t) inhibitor ofBMP antagonism; u) HMG-CoA reductase inhibitor; v) vitamin K orderivative; w) ipriflavone; x) fluoride salts; y) dietary calciumsupplement, and z) osteoprotegerin.

In one embodiment, the methods of this invention are useful in treatingdiseases or disorders caused by, or associated with a hormonal disorder,disruption or imbalance. In one embodiment, the hormonal disorder,disruption or imbalance comprises an excess of a hormone. In anotherembodiment, the hormonal disorder, disruption or imbalance comprises adeficiency of a hormone. In one embodiment, the hormone is a steroidhormone. In another embodiment, the hormone is an estrogen. In anotherembodiment, the hormone is an androgen. In another embodiment, thehormone is a glucocorticoid. In another embodiment, the hormone is acortico-steroid. In another embodiment, the hormone is LuteinizingHormone (LH). In another embodiment, the hormone is Follicle StimulatingHormone (FSH). In another embodiment, the hormone is any other hormoneknown in the art. In another embodiment, the hormonal disorder,disruption or imbalance is associated with menopause. In anotherembodiment, the hormonal disorder, disruption or imbalance is associatedwith andropause, andropausal vasomotor symptoms, andropausalgynecomastia, muscle strength and/or function, bone strength and/orfunction and anger. In another embodiment, hormone deficiency is aresult of specific manipulation, as a byproduct of treating a disease ordisorder in the subject. For example, the hormone deficiency may be aresult of androgen depletion in a subject, as a therapy for prostatecancer in the subject. Each possibility represents a separate embodimentof the present invention.

In another embodiment the invention is directed to treating sarcopeniaor cachexia, and associated conditions related thereto, for examplediseases or disorders of the bone.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for 1) treating a muscle wasting disorder; 2) preventing amuscle wasting disorder; 3) treating, preventing, suppressing,inhibiting or reducing muscle loss due to a muscle wasting disorder; 4)treating, preventing, inhibiting, reducing or suppressing muscle wastingdue to a muscle wasting disorder; and/or 5) treating, preventing,inhibiting, reducing or suppressing muscle protein catabolism due to amuscle wasting disorder; and/or treating, preventing, inhibiting,reducing or suppressing end stage renal disease; and/or 6) treating,preventing, inhibiting, reducing or suppressing frailty.

In another embodiment, the use of a compound for treating a subjecthaving a muscle wasting disorder, or any of the disorders describedherein, includes administering a pharmaceutical composition including acompound as herein described. In another embodiment, the administeringstep includes intravenously, intraarterially, or intramuscularlyinjecting to said subject said pharmaceutical composition in liquidform; subcutaneously implanting in said subject a pellet containing saidpharmaceutical composition; orally administering to said subject saidpharmaceutical composition in a liquid or solid form; or topicallyapplying to the skin surface of said subject said pharmaceuticalcomposition.

A muscle is a tissue of the body that primarily functions as a source ofpower. There are three types of muscles in the body: a) skeletalmuscle—the muscle responsible for moving extremities and external areasof the bodies; b) cardiac muscle—the heart muscle; and c) smoothmuscle—the muscle that is in the walls of arteries and bowel.

A wasting condition or disorder is defined herein as a condition ordisorder that is characterized, at least in part, by an abnormal,progressive loss of body, organ or tissue mass. A wasting condition canoccur as a result of a pathology such as, for example, cancer, or aninfection, or it can be due to a physiologic or metabolic state, such asdisuse deconditioning that can occur, for example, due to prolonged bedrest or when a limb is immobilized, such as in a cast. A wastingcondition can also be age associated. The loss of body mass that occursduring a wasting condition can be characterized by a loss of total bodyweight, or a loss of organ weight such as a loss of bone or muscle massdue to a decrease in tissue protein.

In one embodiment, “muscle wasting” or “muscular wasting”, used hereininterchangeably, refer to the progressive loss of muscle mass and/or tothe progressive weakening and degeneration of muscles, including theskeletal or voluntary muscles which control movement, cardiac muscleswhich control the heart, and smooth muscles. In one embodiment, themuscle wasting condition or disorder is a chronic muscle wastingcondition or disorder. “Chronic muscle wasting” is defined herein as thechronic (i.e. persisting over a long period of time) progressive loss ofmuscle mass and/or to the chronic progressive weakening and degenerationof muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by a muscle protein breakdown or degradation, by muscleprotein catabolism. Protein catabolism occurs because of an unusuallyhigh rate of protein degradation, an unusually low rate of proteinsynthesis, or a combination of both. Protein catabolism or depletion,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. The term “catabolism” has its commonly known meaning in theart, specifically an energy burning form of metabolism.

Muscle wasting can occur as a result of a pathology, disease, conditionor disorder. In one embodiment, the pathology, illness, disease orcondition is chronic. In another embodiment, the pathology, illness,disease or condition is genetic. In another embodiment, the pathology,illness, disease or condition is neurological. In another embodiment,the pathology, illness, disease or condition is infectious. As describedherein, the pathologies, diseases, conditions or disorders for which thecompounds and compositions of the present invention are administered arethose that directly or indirectly produce a wasting (i.e. loss) ofmuscle mass, that is a muscle wasting disorder.

In one embodiment, muscle wasting in a subject is a result of thesubject having a muscular dystrophie; muscle atrophy; X-linkedspinal-bulbar muscular atrophy (SBMA).

The muscular dystrophies are genetic diseases characterized byprogressive weakness and degeneration of the skeletal or voluntarymuscles that control movement. The muscles of the heart and some otherinvoluntary muscles are also affected in some forms of musculardystrophy. The major forms of muscular dystrophy (MD) are: duchennemuscular dystrophy, myotonic dystrophy, duchenne muscular dystrophy,becker muscular dystrophy, limb-girdle muscular dystrophy,facioscapulhumeral muscular dystrophy, congenital muscular dystrophy,oculopharyngeal muscular dystrophy, distal muscular dystrophy andemery-dreifuss muscular dystrophy.

Muscular dystrophy can affect people of all ages. Although some formsfirst become apparent in infancy or childhood, others may not appearuntil middle age or later. Duchenne MD is the most common form,typically affecting children. Myotonic dystrophy is the most common ofthese diseases in adults.

Muscle atrophy (MA) is characterized by wasting away or diminution ofmuscle and a decrease in muscle mass. For example, Post-Polio MA is amuscle wasting that occurs as part of the post-polio syndrome (PPS). Theatrophy includes weakness, muscle fatigue, and pain.

Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA—alsoknown as Kennedy's Disease). This disease arises from a defect in theandrogen receptor gene on the X chromosome, affects only males, and itsonset is in adulthood. Because the primary disease cause is an androgenreceptor mutation, androgen replacement is not a current therapeuticstrategy. There are some investigational studies where exogenoustestosterone propionate is being given to boost the levels of androgenwith hopes of overcoming androgen insensitivity and perhaps provide ananabolic effect. Still, use of supraphysiological levels of testosteronefor supplementation will have limitations and other potentially seriouscomplications.

Sarcopenia is a debilitating disease that afflicts the elderly andchronically ill patients and is characterized by loss of muscle mass andfunction. Further, increased lean body mass is associated with decreasedmorbidity and mortality for certain muscle-wasting disorders. Inaddition, other circumstances and conditions are linked to, and cancause muscle wasting disorders. For example, studies have shown that insevere cases of chronic lower back pain, there is paraspinal musclewasting.

Muscle wasting and other tissue wasting is also associated with advancedage. It is believed that general weakness in old age is due to musclewasting. As the body ages, an increasing proportion of skeletal muscleis replaced by fibrous tissue. The result is a significant reduction inmuscle power, performance and endurance.

Long term hospitalization due to illness or injury, or disusedeconditioning that occurs, for example, when a limb is immobilized, canalso lead to muscle wasting, or wasting of other tissue. Studies haveshown that in patients suffering injuries, chronic illnesses, burns,trauma or cancer, who are hospitalized for long periods of time, thereis a long-lasting unilateral muscle wasting, and a decrease in bodymass.

Injuries or damage to the central nervous system (CNS) are alsoassociated with muscle wasting and other wasting disorders. Injuries ordamage to the CNS can be, for example, caused by diseases, trauma orchemicals. Examples are central nerve injury or damage, peripheral nerveinjury or damage and spinal cord injury or damage. In one embodiment CNSdamage or injury comprise Alzheimer's diseases (AD); anger (mood);anorexia, anorexia nervosa, anorexia associated with aging and/orassertiveness (mood).

In another embodiment, muscle wasting or other tissue wasting may be aresult of alcoholism, and may be treated with the compounds andcompositions of the invention, representing embodiments thereof.

In one embodiment, the invention provides a use of SARM compound asdescribed herein or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof for thetreatment of a wasting disease, disorder or condition in a subject.

In one embodiment, the wasting disease, disorder or condition beingtreated is associated with chronic illness

This invention is directed to treating, in some embodiments, any wastingdisorder, which may be reflected in muscle wasting, weight loss,malnutrition, starvation, or any wasting or loss of functioning due to aloss of tissue mass.

In some embodiments, wasting diseases or disorders, such as cachexia;malnutrition, tuberculosis, leprosy, diabetes, renal disease, chronicobstructive pulmonary disease (COPD), cancer, end stage renal failure,sarcopenia, emphysema, osteomalacia, or cardiomyopathy, may be treatedby the methods of this invention, via the administration of a SARMcompound as herein described, compositions comprising the same, with orwithout additional drugs, compounds, or agents, which provide atherapeutic effect for the condition being treated.

In some embodiments, wasting is due to infection with enterovirus,Epstein-Barr virus, herpes zoster, HIV, trypanosomes, influenze,coxsackie, rickettsia, trichinella, schistosoma or mycobacteria, andthis invention, in some embodiments, provides methods of treatmentthereof.

Cachexia is weakness and a loss of weight caused by a disease or as aside effect of illness. Cardiac cachexia, i.e. a muscle protein wastingof both the cardiac and skeletal muscle, is a characteristic ofcongestive heart failure. Cancer cachexia is a syndrome that occurs inpatients with solid tumors and hematological malignancies and ismanifested by weight loss with massive depletion of both adipose tissueand lean muscle mass.

Cachexia is also seen in acquired immunodeficiency syndrome (AIDS),human immunodeficiency virus (HIV)-associated myopathy and/or muscleweakness/wasting is a relatively common clinical manifestation of AIDS.Individuals with HIV-associated myopathy or muscle weakness or wastingtypically experience significant weight loss, generalized or proximalmuscle weakness, tenderness, and muscle atrophy.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an infection ina subject. In one embodiment, the method comprises administering to asubject a composition comprising a compound and an immunomodulatingagent, an anti-infective agent, a gene therapy agent, or a combinationthereof. In some embodiments, infections comprise actinomycosis,anaplasmosis, anthrax, aspergillosis, bacteremia, bacterial mycoses,bartonella infections, botulism, brucellosis, burkholderia infections,campylobacter infections, candidiasis, cat-scratch disease, chlamydiainfections, cholera, clostridium infections, coccidioidomycosis, crossinfection, cryptococcosis, dermatomycoses, diphtheria, ehrlichiosis,Escherichia coli infections, fasciitis, necrotizing, Fusobacteriuminfections, gas gangrene, gram-negative bacterial infections,gram-positive bacterial infections, histoplasmosis, impetigo, Klebsiellainfections, legionellosis, leprosy, leptospirosis, Listeria infections,lyme disease, maduromycosis, melioidosis, mycobacterium infections,mycoplasma infections, mycoses, nocardia infections, onychomycosis,plague, pneumococcal infections, pseudomonas infections, psittacosis, qfever, rat-bite fever, relapsing fever, rheumatic fever, Rickettsiainfections, rocky mountain spotted fever, salmonella infections, scarletfever, scrub typhus, sepsis, sexually transmitted diseases,Staphylococcal infections, Streptococcal infections, tetanus, tick-bomediseases, tuberculosis, tularemia, typhoid fever, typhus, louse-bome,vibrio infections, yaws, yersinia infections, zoonoses, zygomycosis,acquired immunodeficiency syndrome, adenoviridae infections, alphavirusinfections, arbovirus infections, borna disease, bunyaviridaeinfections, caliciviridae infections, chickenpox, coronaviridaeinfections, coxsackievirus infections, cytomegalovirus infections,dengue, DNA virus infections, eethyma, contagious, encephalitis,arbovirus, Epstein-barr virus infections, erythema infectiosum,hantavirus infections, hemorrhagic fevers, viral hepatitis, viral humanherpes simplex, herpes zoster, herpes zoster oticus, herpesviridaeinfections, infectious mononucleosis, human-lassa fever, measles,molluscum, contagiosum, mumps, paramyxoviridae infections, phlebotomusfever, polyomavirus infections, rabies, respiratory syncytial virusinfections, rift valley fever, RNA virus infections, rubella, slow virusdiseases, smallpox, subacute sclerosing panencephalitis, tumor virusinfections, warts, west nile fever, virus diseases, yellow fever,amebiasis, anisakiasis, ascariasis, babesiosis, blastocystis hominisinfections, bug bite, cestode infections, chagas disease,cryptosporidiosis, cyclosporiasis, cysticercosis, dientamoebiasis,diphyllobothriasis, dracunculiasis, echinococcosis, ectoparasiticinfestations, filariasis, giardiasis, helminthiasis, hookworminfections, larva migrans, leishmaniasis, lice infestations, loiasis,malaria, mite infestations, myiasis, onchocerciasis, protozoaninfections, scabies, schistosomiasis, skin diseases, parasitic,strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, trichinosis,trichomonas infections, trypanosomiasis, trypanosomiasis, african, orwhipworm infections.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with amusculoskeletal disease in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundand an anti-cancer agent, an immunomodulating agent, an antidiabeticagent, an agent treating the central nervous system, an agent treating ametabolic disease, an agent treating a wasting disease, a gene therapyagent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, musculoskeletal diseasescomprise achondroplasia, acquired hyperostosis syndrome,acrocephalosyndactylia, arthritis, arthrogryposis, arthropathy,neurogenic bursitis, cartilage diseases, cleidocranial dysplasia,clubfoot, compartment syndromes, craniofacial dysostosis,craniosynostoses, dermatomyositis, Dupuytren's contracture, dwarfism,Ellis Van Creveld syndrome, enchondromatosis, eosinophilia-myalgiasyndrome, exostoses, fasciitis, fatigue syndrome, fibromyalgia, fibrousdysplasia of bone, fibrous dysplasia, polyostotic, flatfoot, footdeformities, Freiberg's disease, funnel chest, Goldenhar syndrome, gout,hallux valgus, hip dislocation, hyperostosis, intervertebral diskdisplacement, kabuki make-up syndrome, Klippel-Feil syndrome,Langer-Giedion syndrome, Legg-Perthes disease, lordosis, mandibulofacialdysostosis, melorheostosis, mitochondrial myopathies, muscle cramp,muscle spasticity, muscular dystrophies, musculoskeletal abnormalities,musculoskeletal diseases, myositis, myositis ossificans, myotubularmyopathy, osteitis deformans, osteoarthritis, osteochondritis,osteogenesis imperfecta, osteomyelitis, osteonecrosis, osteopetrosis,osteoporosis, poland syndrome, polychondritis, relapsing, polymyalgiarheumatica, polymyositis, rhabdomyolysis, rheumatic diseases, Russellsilver syndrome, Scheuermann's disease, scoliosis, Sever'sdisease/calceneal apophysitis, spinal diseases, spinal osteophytosis,spinal stenosis, spondylitis, ankylosing, spondylolisthesis, sprengel'sdeformity, synovitis, tendinopathy, tennis elbow, tenosynovitis,thanatophoric dysplasia, or Tietze's syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a digestivesystem disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the central nervous system, an agent treating thegastrointestinal system, an anti-infective agent, an agent treating ametabolic disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments,gastrointestinal diseases comprise adenomatous polyposis coli, Alagillesyndrome, anus diseases, appendicitis, barrett esophagus, biliaryatresia, biliary tract diseases, Caroli disease, celiac disease,cholangitis, cholecystitis, cholelithiasis, colitis, ulcerative, Crohn'sdisease, deglutition disorders, duodenal ulcer, dysentery,enterocolitis, pseudomembranous, esophageal achalasia, esophagealatresia, esophagitis, exocrine pancreatic insufficiency, fatty liver,fecal incontinence, gastritis, gastritis, hypertrophic, gastroenteritis,gastroesophageal reflux, gastroparesis, hemorrhoids, hepatic veinthrombosis, hepatitis, hepatitis, chronic, hernia, diaphragmatic,hernia, hiatal, Hirschsprung disease, hypertension (HTN), portal,inflammatory bowel diseases, intestinal diseases, intestinal neoplasms,intestinal neuronal dysplasia, intestinal obstruction, irritable bowelsyndrome, lactose intolerance, liver cirrhosis, liver diseases, meckeldiverticulum, pancreatic diseases, pancreatic neoplasms, pancreatitis,peptic ulcer, Peutz-Jeghers syndrome, proctitis, rectal diseases, rectalprolapse, short bowel syndrome, tracheoesophageal fistula, whippledisease, or Zollinger-Ellison syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a stomatognathicdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an anti-infective agent,an agent treating a wasting disease, a gene therapy agent, an agenttreating the endocrine system, vitamins, or a combination thereof. Insome embodiments, stomatognathic diseases comprise ankyloglossia,bruxism, burning mouth syndrome, cheilitis, cherubism, cleft lip,dentigerous cyst, gingivitis, glossitis, benign migratory, herpeslabialis, Ludwig's angina, macroglossia, Melkersson-Rosenthal syndrome,periodontal diseases, Pierre Robin syndrome, prognathism, salivary glanddiseases, sialorrhea, stomatitis, aphthous, temporomandibular jointdisorders, temporomandibular joint dysfunction syndrome, or xerostomia.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a respiratorytract disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an agent treating thecentral nervous system, an agent treating the cardiovascular system, ananti-infective agent, an agent treating a wasting disease, a genetherapy agent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, respiratory tract diseasescomprise airway obstruction, apnea, asbestosis, asthma, asthma-inducedmuscle weakness or bone weakness, atelectasis, berylliosis, bronchialdiseases, bronchiectasis, bronchiolitis, bronchiolitis obliteransorganizing pneumonia, bronchitis, bronchopulmonary dysplasia, chronicobstructive pulmonary disease (COPD), common cold, cough, empyema,pleural, epiglottitis, glucocorticoid (GC)-induced myopathy orosteopenia hemoptysis, hypertension, pulmonary, hyperventilation,kartagener syndrome, lung abscess, lung diseases, meconium aspirationsyndrome, pleural effusion, pleurisy, pneumonia, pneumothorax, pulmonaryalveolar proteinosis, pulmonary disease, chronic obstructive, pulmonaryedema, pulmonary embolism, pulmonary emphysema, pulmonary fibrosis,respiratory distress syndrome, newborn-respiratory hypersensitivity,respiratory tract infections, rhinoscleroma, scimitar syndrome, severeacute respiratory syndrome, silicosis, sleep apnea, central stridor,tracheal stenosis, decreased muscle mass or bone mass due to asthma,wasting in chronic obstructive pulmonary disease (COPD), Wegener'sgranulomatosis, or whooping cough.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with anotorhinolaryngologic disease in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundand an anti-cancer agent, an immunomodulating agent, an anti-infectiveagent, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, otorhinolaryngologic diseases comprisecholesteatoma, middle ear, croup, deafness, epistaxis, hearing loss,hyperacusis, labyrinthitis, laryngitis, laryngomalacia, laryngostenosis,mastoiditis, Meniere's disease, nasal obstruction, nasal polyps, otitis,otorhinolaryngologic diseases, otoscierosis, pharyngitis, presbycusis,retropharyngeal abscess, rhinitis, sinusitis, tinnitus, tonsillitis,tympanic membrane perforation, vestibular neuronitis, vocal cordparalysis, or voice disorders.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a nervous systemdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an agent treating thecentral nervous system, an anti-infective agent, an agent treating ametabolic disease, an agent treating a wasting disease, a gene therapyagent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, nervous system diseasescomprise autonomic nervous system diseases, central nervous systemdiseases, cranial nerve diseases, demyelinating diseases, nervous systemmalformations, neurologic manifestations, or neuromuscular diseases.

In some embodiments, autonomic nervous system diseases comprisecausalgia, or reflex sympathetic dystrophy.

In some embodiments, central nervous system diseases compriseAlzheimer's disease, arachnoiditis, brain abscess, brain ischemia,central nervous system infections, cerebral palsy, cerebrovasculardisorders, corticobasal ganglionic degeneration (CBGD),Creutzfeldt-Jakob syndrome, Dandy-Walker syndrome, dementia,encephalitis, encephalomyelitis, epilepsy, epilepsy induced hypogonadaland/or hypermetabolic state, essential tremor, Friedreich ataxia,Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz syndrome,Huntington disease, hydrocephalus, hypoxia, insomnia, ischemic attack,kuru, Landau-Kleffner syndrome, Lewy Body disease, Machado-Josephdisease, meige syndrome, meningitis, bacterial meningitis, viral,migraine disorders, movement disorders, multiple system atrophy,myelitis, olivopontocerebellar atrophies, Parkinson's disease,parkinsonian disorders, poliomyelitis, postpoliomyelitis syndrome, priondiseases, pseudotumor cerebri, Shy-Drager syndrome, spasms, infantile,spinal cord diseases, supranuclear palsy, syringomyelia, thalamicdiseases, tic disorders, tourette syndrome, or uveomeningoencephaliticsyndrome. In some embodiments, the central nervous system disease iscystic fibrosis induced hypogonadal state.

In some embodiments, cranial nerve diseases comprise bell palsy, cranialnerve diseases, facial hemiatrophy, facial neuralgia, glossopharyngealnerve diseases, Moebius syndrome, or trigeminal neuralgia.

In some embodiments, central nervous system diseases comprise injuriesor damage to the central nervous system (CNS). In some embodiments,injuries or damage to the CNS may be associated with muscle wastingdisorders. Injuries or damage to the CNS can be, for example, caused bydiseases, trauma or chemicals. Examples are central nerve injury ordamage, peripheral nerve injury or damage and spinal cord injury ordamage.

Studies involving patients with spinal cord injuries (SCI) have shownthat central neurotransmitters may be altered after SCI causinghypothalamus-pituitary-adrenal axis dysfunction, whose disruption led toa significant decrease in testosterone and other hormone levels. SCI orother acute illness or trauma characteristically includes heightenedcatabolism in conjunction with the lowered anabolic activity resultingin a condition that is prone to loss of lean body tissue, which is oftenaccompanied by disturbed nutrient utilization. The effects of the lossof lean body mass include the development of wounds and impaired healingmechanisms, further compounding the problem. Because of poor nutritionand protein combined with immobilization, patients with spinal cordinjury are at high risk for bed sores.

In one embodiment, a wide variety of injuries of the CNS may be treatedby the methods of the present invention. CNS injury may refer, in oneembodiment, to a breakdown of the membrane of a nerve cell, or, inanother embodiment, to the inability of the nerve to produce andpropagate nerve impulses, or in another embodiment, to the death of thecell. An injury includes damage that directly or indirectly affects thenormal functioning of the CNS. The injury may be a structural, physical,or mechanical impairment and may be caused by physical impact, as in thecase of a crushing, compression, or stretching of nerve fibers.Alternatively, the cell membrane may be destroyed by or degraded by anillness, a chemical imbalance, or a physiological malfunction such asanoxia (e.g., stroke), aneurysm, or reperfusion. A CNS injury includes,for example and without limitation, damage to retinal ganglion cells, atraumatic brain injury, a stroke-related injury, a cerebralaneurism-related injury, a spinal cord injury, including monoplegia,diplegia, paraplegia, hemiplegia and quadriplegia, a neuroproliferativedisorder, or neuropathic pain syndrome.

With injury to the spinal cord of a mammal, connections between nervesin the spinal cord are broken. Such injuries block the flow of nerveimpulses for the nerve tracts affected by the injury, with a resultingimpairment to both sensory and motor function. Injuries to the spinalcord may arise from compression or other contusion of the spinal cord,or a crushing or severing of the spinal cord. A severing of the spinalcord, also referred to herein as a “transection,” may be a completesevering or, may be an incomplete severing of the spinal cord.

In some embodiments, the methods of treating a subject suffering form aCNS injury or, in other embodiments, spinal cord injury, may beaccompanied by treatment of the subject with electrical stimulation ofthe injured site and the administration of a purine nucleoside, oranalog thereof, for example as described in United States PatentApplication Publication Number 20040214790A1.

In some embodiments, demyelinating diseases compriseadrenoleukodystrophy, alexander disease, canavan disease, demyelinatingdisease, diffuse cerebral sclerosis of schilder, leukodystrophy-globoidcell, leukodystrophy-metachromatic, multiple sclerosis, or neuromyelitisoptica.

In some embodiments, nervous system malformations comprise Arnold-Chiarimalformation, Charcot-Marie-Tooth disease, encephalocele, hereditarymotor and sensory neuropathies, septo-optic dysplasia, spina bifidaocculta, or spinal dysraphism.

In some embodiments, neurologic manifestations comprise agnosia,amnesia, anomia, aphasia, apraxias, back pain, Brown-Sequard syndrome,cerebellar ataxia, chorea, communication disorders, confusion,dizziness, dyslexia, dystonia, facial paralysis, fasciculation, gaitdisorders, neurologic-headache, hemiplegia, memory disorders, mentalretardation, mutism, myoclonus, neck pain, nonverbal learning disorder,olfaction disorders, pain, paralysis, phantom limb, prosopagnosia,quadriplegia, seizures, spasm, speech disorders, synesthesia tardivedyskinesia, taste disorders, torticollis, tremor, trismus,unconsciousness, or vertigo.

In some embodiments, neuromuscular diseases comprise. amyotrophiclateral sclerosis, brachial plexus neuritis, brachial plexusneuropathies, bulbar palsy, carpal tunnel syndrome, cubital tunnelsyndrome, diabetic neuropathies, dysautonomia, guillain, barre syndrome,hereditary sensory and autonomic neuropathies, miller fisher syndrome,motor neuron disease, muscular atrophy, spinal, myasthenia gravis,myopathies, structural, congenital, nerve compression syndromes,neuralgia, neuromuscular diseases, paralyses, familial periodic,peripheral nervous system diseases, poems syndrome, polyneuropathies,polyradiculopathy, refsum disease, sciatica, spinal muscular atrophiesof childhood, stiff-person syndrome, thoracic outlet syndrome, or ulnarnerve compression syndromes.

In one embodiment, methods of treating a subject with a nervous systemdisease encompass treating any secondary conditions in the subject,which arise due to the subject having a nervous system disease, some ofwhich are described herein.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an ophthalmicdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an agent treating thecardiovascular system, an anti-infective agent, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodimentsophthalmic disease comprise acute zonal occult outer retinopathy, Adiesyndrome, albinism, ocular-amaurosis, fugax, amblyopia, aniridia,anisocoria, anopthalmos, aphakia, astigmatism, blepharitis,blepharoptosis, blepharospasm, blindness, cataract, chalazion,chorioretinitis, choroideremia, coloboma, color vision defects,conjunctivitis, corneal diseases, corneal dystrophies, corneal edema,corneal ulcer, diabetic retinopathy, diplopia, distichiasis, dry eyesyndromes, Duane retraction syndrome, ectropion, entropion, esotropia,exfoliation syndrome, exotropia, eye hemorrhage, eye neoplasms, eyeliddiseases, floaters, general fibrosis syndrome, glaucoma, gyrate atrophy,hemianopsia, Henmanski-Pudlak syndrome, hordeolum, Horner syndrome,hyperopia, hyphema, iritis, Kearns-Sayer syndrome, keratitis,keratoconus, lacrimal apparatus diseases, lacrimal duct obstruction,lens diseases, macular degeneration, micropthalmos, myopia, nystagmus,pathologic, ocular motility disorders, oculomotor nerve diseases,opthalmoplegia, optic atrophies, optic nerve diseases, optic neuritis,optic neuropathy, orbital cellulitis, papilledema, peter's anomaly,presbyopia, pterygium, pupil disorders, refractive errors, retinaldetachment, retinal diseases, retinal vein occlusion, retinitispigmentosa, retinopathy of prematurity, retinoschisis, scleritis,scotoma, strabismus, Thygeson's superficial punctate keratitis,trachoma, uveitis, white dot syndrome, vision disorders, or vitreousdisorders

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an urologicand/or male genital disease in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundand an anti-cancer agent, an immunomodulating agent, an antidiabeticagent, an agent treating the gastrointestinal system, an anti-infectiveagent, an agent treating the kidney, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, an urologic and/or male genital diseases compriseanti-glomerular basement membrane disease, balanitis, bladder exstrophy,bladder neoplasms, cryptorchidism, cystitis, interstitial, diabetesinsipidus, nephrogenic, epididymitis, fournier gangrene,glomerulonephritis, Goodpasture syndrome, hematospermia, hematuria,hemolytic-uremic syndrome, hydronephrosis, hypospadias, impotence,infertility, kidney calculi, kidney failure, acute, kidney failure,chronic, kidney tubular necrosis, acute, medullary sponge kidney,multicystic dysplastic kidney, nephritis, hereditary, nephrosis,nephrotic syndrome, nocturia, oliguria, penile diseases, penileinduration, penile neoplasms, phimosis, priapism, prostatic diseases,benign prostate hyperplasia, prostatic neoplasms, proteinuria,pyelonephritis, Reiter disease, renal artery obstruction, spermatic cordtorsion, testicular diseases, urethral stricture, urethritis, urinaryretention, urinary tract infections, urination disorders, urologic andmale genital diseases, urologic diseases, varicocele, vesico, orurethral reflux.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a dermatologicaldisorder in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound andanti-cancer agent, an immunomodulating agent, an agent treating adermatological disorder, an anti-infective agent, a gene therapy agent,an agent treating the endocrine system, vitamins, or a combinationthereof. In some embodiments, dermatological disorders comprise acne,actinic keratosis, alopecia, androgenic alopecia, alopecia greata,alopecia secondary to chemotherapy, alopecia secondary to radiationtherapy, alopecia induced by scarring, alopecia induced by stress,angioma, athlete's foot, aquagenic pruritus, atopic dermatitis,baldness, premature baldness, male pattern baldness, androgenicbaldness, basal cell carcinoma, burns, bed sore, Behcet's disease,blepharitis, boil, Bowen's disease, bullous pemphigoid, canker sore,carbuncles, cellulitis, chloracne, chronic dermatitis of the hands andfeet, dyshidrosis, cold sores, contact dermatitis, creeping eruption,dandruff, dermatitis, dermatitis herpetiformis, dermatofibroma, diaperrash, eczema, epidermolysis bullosa, erysipelas, erythroderma, frictionblister, genital wart, hidradenitis, suppurativa, hives, hyperhidrosis,ichthyosis, impetigo, jock itch, Kaposi's sarcoma, keloid,keratoacanthoma, keratosis pilaris, lice infection, lichen planus,lichen simplex chronicus, lipoma, lymphadenitis, malignant melanoma,melasma, miliaria, molluscum contagiosum, nummular dermatitis, paget'sdisease of the nipple, pediculosis, pemphigus, perioral dermatitis,photoallergy, photosensitivity, pityriasis rosea, pityriasis rubrapilaris, psoriasis, raynaud's disease, ring worm, rosacea, scabies,scleroderma, sebaceous cyst, seborrheic keratosis, seborrhoeicdermatitis, shingles, skin cancer, skin tags, spider veins, squamouscell carcinoma, stasis dermatitis, tick bite, tinea barbae, tineacapitis, tinea corporis, tinea cruris, tinea pedis, tinea unguium, tineaversicolor, tinea, tungiasis, vitiligo, or warts.

In one embodiment, the dermatological disorder is a wound or a burn. Insome embodiments, wounds and/or ulcers are found protruding from theskin or on a mucosal surface or as a result of an infarction in anorgan. A wound may be a result of a soft tissue defect or a lesion or ofan underlying condition. In one embodiment, the term “wound” denotes abodily injury with disruption of the normal integrity of tissuestructures. The term is also intended to encompass the terms “sore”,“lesion”, “necrosis” and “ulcer”. In one embodiment, the term “sore”refers to any lesion of the skin or mucous membranes and the term“ulcer” refers to a local defect, or excavation, of the surface of anorgan or tissue, which is produced by the sloughing of necrotic tissue.Lesion generally relates to any tissue defect. Necrosis is related todead tissue resulting from infection, injury, inflammation orinfarctions. All of these are encompassed by the term “wound”, whichdenotes any wound at any particular stage in the healing processincluding the stage before any healing has initiated or even before aspecific wound like a surgical incision is made (prophylactictreatment).

Examples of wounds which can be prevented and/or treated in accordancewith the present invention are, e.g., aseptic wounds, contused wounds,incised wounds, lacerated wounds, non-penetrating wounds (i.e. wounds inwhich there is no disruption of the skin but there is injury tounderlying structures), open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds, subcutaneous wounds, etc.Examples of sores are bed sores, canker sores, chrome sores, cold sores,pressure sores etc. Examples of ulcers are, e.g., peptic ulcer, duodenalulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemiculcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer,submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer,veneral ulcer, e.g. caused by gonorrhoea (including urethritis,endocervicitis and proctitis). Conditions related to wounds or soreswhich may be successfully treated according to the invention are burns,anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae,folliculitis, impetigo contagiosa, or impetigo bullosa, etc. There isoften a certain overlap between the use of the terms “wound” and “ulcer”and “wound” and “sore” and, furthermore, the terms are often used atrandom. Therefore as mentioned above, in the present context the term“wounds” encompasses the term “ulcer”, “lesion”, “sore” and“infarction”, and the terms are indiscriminately used unless otherwiseindicated.

The kinds of wounds to be treated according to the invention includealso i) general wounds such as, e.g., surgical, traumatic, infectious,ischemic, thermal, chemical and bullous wounds; ii) wounds specific forthe oral cavity such as, e.g., post-extraction wounds, endodontic woundsespecially in connection with treatment of cysts and abscesses, ulcersand lesions of bacterial, viral or autoimmunological origin, mechanical,chemical, thermal, infectious and lichenoid wounds; herpes ulcers,stomatitis aphthosa, acute necrotising ulcerative gingivitis and burningmouth syndrome are specific examples; and iii) wounds on the skin suchas, e.g., neoplasm, burns (e.g. chemical, thermal), lesions (bacterial,viral, autoimmunological), bites and surgical incisions. Another way ofclassifying wounds is as i) small tissue loss due to surgical incisions,minor abrasions and minor bites, or as ii) significant tissue loss. Thelatter group includes ischemic ulcers, pressure sores, fistulae,lacerations, severe bites, thermal burns and donor site wounds (in softand hard tissues) and infarctions.

In other aspects of the invention, the wound to be prevented and/ortreated is selected from the group consisting of aseptic wounds,infarctions, contused wounds, incised wounds, lacerated wounds,non-penetrating wounds, open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds and subcutaneous wounds.

Other wounds which are of importance in connection with the presentinvention are wounds like ischemic ulcers, pressure sores, fistulae,severe bites, thermal burns and donor site wounds.

In one embodiment, the compound as described herein is useful in woundhealing as an adjunct to physical therapy/rehabilitation, as an anabolicagent. In another embodiment, the compound as described herein is usefulin promoting healing of anterior cruciate ligament (ACL) or medialcruciate ligament (MCL) injuries, or accelerating recovery after ACL orMCL surgery. In another embodiment, the compound as described herein isuseful in enhancing athletic performance. In another embodiment, thecompound as described herein is useful in treating burns. In anotherembodiment, the compound as described herein is useful in stimulatingcartilage regrowth. In another embodiment, the compound as describedherein is useful in preventing, treating, or reversing of catabolismassociated with prolonged critical illness, pulmonary dysfunction,ventilator dependency, aging, AIDS, trauma, surgery, congestive heartfailure, cardiac myopathy, burns, cancer, COPD. In another embodiment,the compound as described herein is useful in preventing or reversingprotein catabolism due to trauma. In another embodiment, the compound asdescribed herein is useful as a) adjunct to cauterization therapy (laseror radio) as is used in surgery to promote wound healing, b) adjunct tocryotherapy to promote wound healing, c) adjunct to chemotherapy toprevent side effects such as alopecia, hypogonadism, muscle wasting,osteopenia, osteoporosis, sarcopenia, increased LDL, TG or totalcholesterol, decreased HDL. In another embodiment, the compound asdescribed herein is useful in chronic catabolic state (coma, wastingconditions, starvation, eating disorders); concomitant bone fracture andmuscle damage; critical illness in which muscle or bone wasting areapparent; and/or connective tissue diseases and disorders.

Ischemic ulcers and pressure sores are wounds, which normally only healvery slowly and especially in such cases an improved and more rapidhealing is of course of great importance for the patient. Furthermore,the costs involved in the treatment of patients suffering from suchwounds are markedly reduced when the healing is improved and takes placemore rapidly.

Donor site wounds are wounds which e.g. occur in connection with removalof hard tissue from one part of the body to another part of the bodye.g. in connection with transplantation. The wounds resulting from suchoperations are very painful and an improved healing is therefore mostvaluable.

The term “skin” is used in a very broad sense embracing the epidermallayer of the skin and in those cases where the skin surface is more orless injured also the dermal layer of the skin. Apart from the stratumcorneum, the epidermal layer of the skin is the outer (epithelial) layerand the deeper connective tissue layer of the skin is called the dermis.

In some embodiments, burns are associated with reduced testosteronelevels, and hypgonadism is associated with delayed wound healing. In oneembodiment, the methods of this invention, provide for treating asubject suffering from a wound or a burn.

In some embodiments, the present invention provides a method forprooting healing of anterior cruciate ligament (ACL) or medial cruciateligament (MCL) injuries, or accelerating recovery after ACL or MCLsurgery.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an endocrinedisorder in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound andanti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating a dermatological disorder, anagent treating the central nervous system, an anti-infective agent, anagent treating the liver, an agent treating the kidney, an agenttreating a metabolic disease, an agent treating a wasting disease, agene therapy agent, an agent treating the endocrine system, vitamins, ora combination thereof. In some embodiments, endocrine disorders compriseacromegaly, Addison disease, adrenal gland diseases, adrenalhyperplasia, congenital, androgen-insensitivity syndrome, congenitalhypothyroidism, Cushing syndrome, diabetes insipidus, diabetes mellitus,diabetes mellitus-type 1, diabetes mellitus-type 2, diabetic,ketoacidosis, empty Sella syndrome, endocrine gland neoplasms, endocrinesystem diseases, gigantism, gonadal disorders, graves disease,hermaphroditism, hyperaldosteronism, hyperglycemic hyperosmolarnonketotic coma, hyperpituitarism, hyperprolactinemia, hyperthyroidism,hypogonadism, hypopituitarism, hypothyroidism, Kallmann syndrome, Nelsonsyndrome, parathyroid diseases, pituitary diseases,polyendocrinopathies, autoimmune, puberty, delayed, puberty, precocious,renal osteodystrophy, thyroid diseases, thyroid hormone resistancesyndrome, thyroid neoplasms, thyroid nodule, thyroiditis, thyroiditis,autoimmune, thyroiditis, subacute, or Wolfram syndrome.

In one embodiment, “Hypogonadism” is a condition resulting from orcharacterised by abnormally decreased functional activity of the gonads,with retardation of growth and sexual development.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with urogenitaldisease and/or fertility in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and anti-cancer agent, an immunomodulating agent, ananti-infective agent, an agent treating the kidney, gene therapy agent,an agent treating the endocrine system, vitamins, or a combinationthereof. In some embodiments, urogenital diseases and/or fertilitydiseases comprise abortion, spontaneous-adhesions-pelvic, candidiasis,vulvovaginal, depression-postpartum, diabetes, gestational, dyspareunia,dystocia, eclampsia, endometriosis, fetal death, fetal growthretardation, fetal membranes, premature rupture, genital diseases,female, genital neoplasms, female, hydatidiform mole, hyperemesisgravidarum, infertility, ovarian cysts, ovarian torsion, pelvicinflammatory disease, placenta diseases, placental insufficiency,polycystic ovary syndrome, polyhydramnios, postpartum hemorrhage,pregnancy complications, pregnancy, ectopic, pruritus vulvae, puerperaldisorders, puerperal infection, salpingitis, trophoblastic neoplasms,uterine cervix incompetence, uterine inversion, uterine prolapse,vaginal diseases, vulvar diseases, vulvar lichen sclerosis.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with hemic and/orlymphatic disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and an anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, ananti-infective agent, an agent treating the liver, an agent treating thekidney, an agent treating a metabolic disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, hemic and/or lymphatic diseases compriseafibrinogenemia, anemia, aplastic anemia, hemolytic anemia, congenitalnonspherocytic anemia, megaloblastic anemia, pernicious anemia, sicklecell anemia, renal anemia, angiolymphoid hyperplasia with eosinophilia,antithrombin III deficiency, Bernard-Soulier syndrome, blood coagulationdisorders, blood platelet disorders, blue rubber bleb nevus syndrome,Chediak-Higashi syndrome, cryoglobulinemia, disseminated intravascularcoagulation, eosinophilia, Erdheim-Chester disease, erythroblastosis,fetal, evans syndrome, factor V deficiency, factor VII deficiency,factor X deficiency, factor XI deficiency, factor XII deficiency,fanconi anemia, giant lymph node hyperplasia, hematologic diseases,hemoglobinopathies, hemoglobinuria, paroxysmal, hemophilia a, hemophiliab, hemorrhagic disease of newborn, histiocytosis, histiocytosis,langerhans-cell, histiocytosis, non-langerhans-cell, job's syndrome,leukopenia, lymphadenitis, lymphangioleiomyomatosis, lymphedema,methemoglobinemia, myelodysplastic syndromes, myelofibrosis, myeloidmetaplasia, myeloproliferative disorders, neutropenia, paraproteinemias,platelet storage pool deficiency, polycythemia vera, protein cdeficiency, protein s deficiency, purpura, thrombocytopenic, purpura,thrombotic thrombocytopenic, RH-isoimmunization, sarcoidosis,sarcoidosis, spherocytosis, splenic rupture, thalassemia,thrombasthenia, thrombocytopenia, Waldenstrom macroglobulinemia, or VonWillebrand disease.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a congenital,hereditary, or neonatal disease in a subject. In one embodiment, themethod comprises administering to a subject a composition comprising acompound of this invention and anti-cancer agent, an immunomodulatingagent, an antidiabetic agent, an agent treating the cardiovascularsystem, an agent treating the gastrointestinal system, an agent treatinga dermatological disorder, an agent treating the central nervous system,an anti-infective agent, an agent treating the liver, an agent treatingthe kidney, an agent treating a metabolic disease, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments,congenital, hereditary, and neonatal diseases comprise Aicardi syndrome,amniotic band syndrome, anencephaly, Angelman syndrome, ataxiatelangiectasiai, Bannayan-Zonana syndrome, Barth syndrome, basal cellnevus syndrome, Beckwith-Wiedemann syndrome, bloom syndrome,branchio-oto-renal syndrome, cat eye syndrome, cerebral gigantism-chargesyndrome, chromosome 16 abnormalities, chromosome 18 abnormalities,chromosome 20 abnormalities, chromosome 22 abnormalities, Costellosyndrome, cri-du-chat syndrome, Currarino syndrome, cystic fibrosis,de-Lange syndrome, distal trisomy 10q, down syndrome, ectodermaldysplasia, fetal alcohol syndrome, fetal diseases, fetofetaltransfusion, fragile x syndrome, Freeman-Sheldon syndrome,gastroschisis, genetic diseases, inborn, hernia, umbilical,holoprosencephaly, incontinentia pigmenti, Ivemark syndrome, Jacobsensyndrome, jaundice, Klinefelter syndrome, Larsen syndrome, Laurence-moonsyndrome, lissencephaly, microcephaly, monosomy 9p, nail-patellasyndrome, neurofibromatoses, neuronal ceroid-lipofuscinosis, Noonansyndrome, ochoa syndrome (urofacial syndrome, hydronephrosis withpeculiar facial expression), oculocerebrorenal syndrome,Pallister-Killian syndrome, Prader-Willi syndrome, proteus syndrome,prune belly syndrome, Rett syndrome, Robinow syndrome, Rubinstein-Taybisyndrome, schizencephaly, situs inversus, Smith-Lemli-Opitz syndrome,Smith-Magenis syndrome, Sturge-Weber syndrome, syphilis, congenital,trichothiodystrophy, triple-x females, trisomy 13 (Patau syndrome),trisomy 9, turner syndrome, twins, conjoined, Usher syndrome,Waardenburg's syndrome, Werner syndrome, or Wolf-Hirschhorn syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a connectivetissue disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and anti-cancer agent, an immunomodulating agent, an agenttreating a dermatological disorder, an anti-infective agent, an agenttreating a metabolic disease, an agent treating a wasting disease, agene therapy agent, an agent treating the endocrine system, vitamins, ora combination thereof. In some embodiments, connective tissue diseasescomprise ankylosing spondylitis, Ehlers-Danlos syndrome,Henoch-Schonlein purpura, Kawasaki disease, Marfan syndrome,polyarteritis nodosa, polymyositis, psoriatic arthritis, reactivearthritis, rheumatoid arthritis, scleroderma, Sjogren's syndrome,xerophthalmia, Still's disease, systemic lupus erythematosus, Takayasudisease, or Wegener's granulomatosis.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a metabolicdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and antidiabetic agent, an agent treating the gastrointestinalsystem, an agent treating a dermatological disorder, an agent treatingthe central nervous system, an anti-infective agent, an agent treatingthe liver, an agent treating the kidney, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, metabolic diseases comprise acid-base imbalance,acidosis, alkalosis, alkaptonuria, alpha-mannosidosis, amino acidmetabolism inborn errors, amyloidosis, iron-deficiency anemia, ascorbicacid deficiency, avitaminosis, beriberi, biotinidase deficiency,carbohydrate-deficient glycoprotein syndrome, carnitine disorders,cystinosis, cystinuria, dehydration, fabry disease, fatty acid oxidationdisorders, fucosidosis, galactosemias, Gaucher disease, Gilbert disease,glucosephosphate dehydrogenase deficiency, glutaric acidemia, glycogenstorage disease, Hartnup disease, hemochromatosis, hemosiderosis,hepatolenticular degeneration, histidinemia, homocystinuria,hyperbilirubinemia, hypercalcemia, hyperinsulinism, hyperkalemia,hyperlipidemia, hyperoxaluria, hypervitaminosis A, hypocalcemia,hypoglycemia, hypokalemia, hyponatremia, hypophosphatasia, insulinresistance, iodine deficiency, iron overload, jaundice, chronicidiopathic, leigh disease, lesch-nyhan syndrome, leucine metabolismdisorders, lysosomal storage diseases, magnesium deficiency, maple syrupurine disease, Melas syndrome, Menkes kinky hair syndrome, metabolicdiseases, metabolic syndrome x, metabolism, inborn errors, mitochondrialdiseases, mucolipidoses, mucopolysaccharidoses, Niemann-Pick diseases,obesity, ornithine carbamoyltransferase deficiency disease,osteomalacia, pellagra, peroxisomal disorders, phenylketonurias,porphyria, erythropoietic, porphyrias, progeria, pseudo, gaucherdisease, refsum disease, Reye syndrome, rickets, Sandhoff disease,starvation, tangier disease, Tay-Sachs disease, tetrahydrobiopterindeficiency, trimethylaminuria, tyrosinemias, urea cycle disorders,water-electrolyte imbalance, Wernicke encephalopathy, vitamin Adeficiency, vitamin B12 deficiency, vitamin B deficiency, Wolmandisease, or Zellweger syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a disorder ofenvironmental origin in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating adermatological disorder, an agent treating the central nervous system,an anti-infective agent, an agent treating the liver, an agent treatingthe kidney, an agent treating a metabolic disease, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments,disorders of environmental origin comprise barotrauma, bites and stings,brain concussion, burns, central cord syndrome, craniocerebral trauma,electric injuries, fractures, bone, frostbite, heat stress disorders,motion sickness, occupational diseases, poisoning, shaken baby syndrome,shoulder injuries, space motion sickness, spinal cord injuries, tickparalysis, or wounds (penetrating and non-penetrating).

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a behaviormechanism in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and an agent treating the cardiovascular system, an agenttreating the central nervous system, a gene therapy agent, an agenttreating the endocrine system, vitamins, or a combination thereof. Insome embodiments, behavior mechanisms comprise aggression, attitude todeath, codependency, self-injurious behavior, sexual behavior, or socialbehavior.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a mentaldisorder in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and an agent treating the central nervous system, a genetherapy agent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, mental disorders compriseAsperger syndrome, attention deficit disorder with hyperactivity,autistic disorder, bipolar disorder, borderline personality disorder,capgras syndrome, child behavior disorders, combat disorders,cyclothymic disorder, dependent personality disorder, depressivedisorder, dissociative disorders, dysthymic disorder, eating disorders,firesetting behavior, hypochondriasis, impulse control disorders,Kleine-Levin syndrome, mental disorders, mental disorders diagnosed inchildhood, multiple personality disorder, Munchausen syndrome,Munchhausen syndrome, narcissistic personality disorder, narcolepsy,obsessive-compulsive disorder, paraphilias, phobic disorders, psychoticdisorders, restless legs syndrome, schizophrenia, seasonal affectivedisorder, sexual and gender disorders, sexual dysfunctions,psychological, sleep disorders, somatoform disorders, stress disorders,post-traumatic, substance-related disorders, suicidal behavior, ortrichotillomania.

In one embodiment, “depression” refers to an illness that involves thebody, mood and thoughts that affects the way a person eats, sleeps andthe way one feels about oneself, and thinks about things. The signs andsymptoms of depression include loss of interest in activities, loss ofappetite or overeating, loss of emotional expression, an empty mood,feelings of hopelessness, pessimism, guilt or helplessness, socialwithdrawal, fatigue, sleep disturbances, trouble concentrating,remembering, or making decisions, restlessness, irritability, headaches,digestive disorders or chronic pain.

In one embodiment, “cognition” refers to the process of knowing,specifically the process of being aware, knowing, thinking, learning andjudging. Cognition is related to the fields of psychology, linguistics,computer science, neuroscience, mathematics, ethology and philosophy. Inone embodiment, “mood” refers to a temper or state of the mind. Ascontemplated herein, alterations mean any change for the positive ornegative, in cognition and/or mood.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a liver diseasein a subject. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention andanti-cancer agent, an immunomodulating agent, an agent treating thegastrointestinal system, an anti-infective agent, an agent treating theliver, an agent treating a metabolic disease, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments, liverdiseases comprise liver cancer, primary biliary cirrhosis, autoimmunehepatitis, chronic liver disease, cirrhosis of the liver, hepatitis,viral hepatitis (hepatitis a, hepatitis b, chronic hepatitis b,hepatitis c, chronic hepatitis c, hepatitis d, hepatitis e, hepatitisx), liver failure, jaundice, neonatal jaundice, hepatoma, liver cancer,liver abscess, alcoholic liver disease, hemochromatosis, Wilson'sdisease, portal hypertension, primary sclerosing cholangitis,sarcoidosis, tapeworms, alveolar hydatid disease, fascioliasis,schistosomiasis, gaucher disease, Zellweger syndrome, alcoholism, foodpoisoning, pneumococcal pneumonia′ or vibrio vulnificus.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a kidney diseasein a subject. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention andanti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the gastrointestinal system, an anti-infective agent, anagent treating the kidney, an agent treating a metabolic disease, a genetherapy agent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, kidney diseases compriseacromegaly, acute renal failure (ARF) amyloidosis, autosomal dominantpolycystic kidney disease, kidney stones, kidney cysts, autosomalrecessive polycystic kidney disease, chronic renal failure (CRF),chronic renal disease, coffin-Lowry syndrome, cor pulmonale,cryoglobulinemia, diabetic nephropathy, dyslipidemia, Gaucher disease,glomerulonephritis, goodpasture syndrome, hemolytic uremic syndrome,hepatitis, kidney cancer, kidney stones, leukemia, lipoproteinemia,lupus, multiple myeloma, nephritis, polyartekidney cysts, poststreptococcal glomerulonephritis, glomerulonephritis, kidney pain,preeclampsia, renal tuberculosis, pyelonephritis, renal tubular acidosiskidney disease, streptococcal toxic shock syndrome, thromboembolism,toxoplasmosis, urinary tract infections, vesicoureteral reflux, orwilliams syndrome.

In one embodiment, the kidney disease or disorder is acute, or inanother embodiment, chronic. In one embodiment, clinical indications ofa kidney disease or disorder, wherein the methods of treatment may beuseful include urinary casts, measured GFR, or other markers of renalfunction.

In one embodiment, the methods of this invention are useful in subjectspredisposed to kidney diseases or disorders. In one embodiment, thephrase “predisposed to a kidney disease or disorder” with respect to asubject is synonymous with the phrase “subject at risk”, and includes asubject at risk of acute or chronic renal failure, or at risk of theneed for renal replacement therapy, if the subject is reasonablyexpected to suffer a progressive loss of renal function associated withprogressive loss of functioning nephron units. Whether a particularsubject is at risk is a determination which may routinely be made by oneof ordinary skill in the relevant medical or veterinary art.

In one embodiment, subjects with kidney disease, in particular malesubjects with end-stage renal disease (ESRD) suffer from hypogonadism,with some having concomitant moderate to severe protein-energymalnutrition (PEM), which leads to higher required doses of EPO, lowerQOL scores, and higher mortality. Many have other symptoms associatedwith hypogonadism, including fatigue, lack of apetite, muscle weakness,etc. In some embodiments, the treatment methods of this invention areuseful in treating symptoms associated with hypogonadism, brought aboutin the subject by androgen deficiency in a female (ADIF); androgendeficiency in aging male (ADAM) to include fatigue, depression,decreased libido, erectile dysfunction, decreased cognition, decreasedmood; androgen insufficiency (male or female), androgen deficiency (maleor female).

In one embodiment, diabetic nephropathy is a complication of diabetesthat evolves early, typically before clinical diagnosis of diabetes ismade. The earliest clinical evidence of nephropathy is the appearance oflow but abnormal levels (>30 mg/day or 20 μg/min) of albumin in theurine (microalbuminuria), followed by albuminuria (>300 mg/24 h or 200μg/min) that develops over a period of 10-15 years. In patients withtype 1 diabetes, diabetic hypertension typically becomes manifest earlyon, by the time that patients develop microalbuminuria. Once overtnephropathy occurs, the glomerular filtration rate (GFR) falls over acourse of times, which may be several years, resulting in End StageRenal Disease (ESRD) in diabetic individuals.

Hypertension is another comorbid factor for renal disease. In someembodiments, treatment of renal disease according to the presentinvention may comprise concomitant treatment with a compound of thisinvention and an agent which treats hypertension.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a wastingdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating thecentral nervous system, an agent treating a metabolic disease, an agenttreating a wasting disease, a gene therapy agent, an agent treating theendocrine system, vitamins, or a combination thereof. In someembodiments, wasting diseases comprise muscle injury, bed rest,immobility, nerve injury, neuropathy, diabetic neuropathy, alcoholicneuropathy, subacute combined degeneration of the spinal cord, diabetes,rheumatoid arthritis, motor neurone diseases, Duchenne musculardystrophy, carpal tunnel syndrome, chronic infection, tuberculosis,Addison's disease, adult sma, limb muscle atrophy, alcoholic neuropathy,anorexia, anorexia nervosa, anorexia associated with cachexia, anorexiaassociated with aging, back tumour, dermatomyositis, hip cancer,inclusion body myositis, incontinentia pigmenti, intercostal neuralgia,juvenile rheumatoid arthritis, Legg-Calve-Perthes disease, muscleatrophy, multifocal motor neuropathy, nephrotic syndrome, osteogenesisimperfecta, post-polio syndrome, rib tumor, spinal muscular atrophy,reflex sympathetic dystrophy syndrome, or Tay-Sachs.

A wasting condition or disorder is defined herein as a condition ordisorder that is characterized, at least in part, by an abnormal,progressive loss of body, organ or tissue mass. A wasting condition canoccur as a result of a pathology such as, for example, cancer, or it canbe due to a physiologic or metabolic state, such as disusedeconditioning that can occur, for example, due to prolonged bed rest orwhen a limb is immobilized, such as in a cast, or with the occurrence ofmultiple wounds, including, for example, amputation, as occurs indiabetics, and other conditions, as will be appreciated by one skilledin the art. A wasting condition can also be age associated. The loss ofbody mass that occurs during a wasting condition can be characterized bya loss of total body weight, or a loss of organ weight such as a loss ofbone or muscle mass due to a decrease in tissue protein.

In one embodiment, the terms “muscle wasting” or “muscular wasting”,refer to the progressive loss of muscle mass and/or to the progressiveweakening and degeneration of muscles, including the skeletal orvoluntary muscles which control movement, cardiac muscles which controlthe heart, and smooth muscles. In one embodiment, the muscle wastingcondition or disorder is a chronic muscle wasting condition or disorder.“Chronic muscle wasting” is defined herein as the chronic (i.e.persisting over a long period of time) progressive loss of muscle massand/or to the chronic progressive weakening and degeneration of muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by a muscle protein breakdown or degradation, by muscleprotein catabolism. Protein catabolism occurs because of an unusuallyhigh rate of protein degradation, an unusually low rate of proteinsynthesis, or a combination of both. Protein catabolism or depletion,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. The term “catabolism” has its commonly known meaning in theart, specifically an energy burning form of metabolism.

Muscle wasting can occur as a result of pathology, disease, condition ordisorders, including disorders for treatment via the methods of thisinvention, such as, for example, end stage renal failure.

In some embodiments, the present invention provides a method forprevention of statin induced rhabdomyolysis. In some embodiments, thepresent invention provides a method for prevention of statin inducedrhabdomyolysis, organ failure or insufficiency. In some embodiments, thepresent invention provides a method for prevention of statin inducedkidney or liver failure or insufficiency. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and a statin.

In one embodiment, the wasting disease is cachexia or involuntary weightloss in a subject. In another embodiment, the present invention providesa method of treating, preventing, inhibiting, reducing or suppressingmuscle wasting in a subject suffering from a kidney disease. In oneembodiment, the present invention provides a method of treating,preventing, inhibiting, reducing or suppressing protein catabolism in asubject suffering from a kidney disease or disorder,

Cachexia is weakness and a loss of weight caused by a disease or as aside effect of illness. Long term hospitalization due to illness orinjury, or disuse deconditioning that occurs, for example, when a limbis immobilized, can also lead to muscle wasting. Studies have shown thatin patients suffering injuries, chronic illnesses, burns, trauma orcancer, who are hospitalized for long periods of time, there is along-lasting unilateral muscle wasting, with a consequent decrease inbody mass. Nervous system injury, for example, spinal cord injury, asdescribed further herein, may be a contributory factor, as well.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a wastingdiseases or disorders in a subject. In another embodiment, the wastingdiseases and disorders include inter-alia: a) acquired immunodeficiencysyndrome (AIDS) wasting; b) wasting associated with bed rest; c)bulimia, and/or wasting associated with bulimia; c) cachexia; d) cancercachexia; e) HIV wasting; f) reduce cachexia and protein loss due toprolonged critical illness, pulmonary dysfunction, ventilatordependency, aging, AIDS, trauma, surgery, congestive heart failure,cardiac myopathy, burns, cancer, chronic obstructive pulmonary disease(COPD), eating disorders such bulimia, anorexia nervosa, loss ofappetite, starvation, and/or depression.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with invalid statesin a subject. In one embodiment, the invalid state is post-poliosyndrome. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention and animmunomodulating agent, an antidiabetic agent, an agent treating thecardiovascular system, an agent treating the gastrointestinal system, anagent treating the central nervous system, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a hypogonadalstate in a subject. In one embodiment, the present invention provides amethod for treating, reducing the incidence, delaying the onset orprogression, or reducing and/or abrogating the symptoms associated witha pharmacotherapy induced hypogonadal state in a subject. In someembodiments, hypogonadism is caused by treatments which alter thesecretion of hormones from the sex glands in both women and men. In someembodiments, hypogonadism may be “primary” or “central”. In primaryhypogonadism, the ovaries or testes themselves do not function properly.In some embodiments, hypogonadism may be induced by surgery, radiation,genetic and developmental disorders, liver and kidney disease,infection, or certain autoimmune disorders. In some embodiments,menopause is a form of hypogonadism. Menopause may cause, in someembodiments, amenorrhea, hot flashes, vaginal dryness, or irritabilitydue to woman's estrogen levels fall. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and an anti-cancer agent, an immunomodulating agent,an antidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating thecentral nervous system, an agent treating a metabolic disease, an agenttreating a wasting disease, a gene therapy agent, an agent treating theendocrine system, an agent treating a dermatological disorder, ananti-infective agent, an agent treating the liver, an agent treating thekidney, vitamins, or a combination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with osteopenic statein a subject. In one embodiment, the present invention provides a methodfor treating, reducing the incidence, delaying the onset or progression,or reducing and/or abrogating the symptoms associated with apharmacotherapy induced osteopenic state in a subject. In someembodiments, osteopenia is a mild thinning of the bone mass. In someembodiments, osteopenia is a precursor to osteoporosis. In someembodiments osteopenia is defined as a bone density between one standarddeviation (SD) and 2.5 SD below the bone density of a normal youngadult. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention and ananti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins, or acombination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a sarcopenicstate in a subject. In one embodiment, the present invention provides amethod for treating, reducing the incidence, delaying the onset orprogression, or reducing and/or abrogating the symptoms associated witha pharmacotherapy induced sarcopenic state in a subject. In someembodiments, sarcopenia is a significant loss of muscle mass. In oneembodiment, sarcopenia definition is having a lean body mass less thantwo standard deviation below the mean for normal young adults. In someembodiments, sarcopenia is caused by genetic factors, alteredcirculation, decrease in the capillary:muscle fiber ratio, altered motorneurons, denervation, deterioration of motor end plates, selectivereinnervation of Type I fibers, inflammatory responses causing muscledamage, reduced exercise, malnutrition, low dietary protein intake,vitamin D deficiency, age-related decline in vitamin D, oxidativestress, muscle mitochondrial mutations, changes in specific types ofmuscle fibers, decline in muscle protein, disabling disease, strokes,Alzheimer's disease, Parkinson's disease, osteoporsis, atherosclerosis,diabetes mellitus, hyperinsulimemia, renal failure, or hypogonadism. Inone embodiment, the method comprises administering to a subject acomposition comprising a SARM compound and an anti-cancer agent, animmunomodulating agent, an antidiabetic agent, an agent treating thecardiovascular system, an agent treating the gastrointestinal system, anagent treating the central nervous system, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, an agent treating a dermatologicaldisorder, an anti-infective agent, an agent treating the liver, an agenttreating the kidney, vitamins, or a combination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a combination ofdiseases and/or disorders in a subject as described hereinabove. In oneembodiment, the method comprises administering to a subject acomposition comprising a compound of this invention and an anti-canceragent, an immunomodulating agent, an antidiabetic agent, an agenttreating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins, or acombination thereof.

It is to be understood that any method of this invention, as hereindescribed, encompasses the administration of a compound as hereindescribed, or a composition comprising the same, to the subject, inorder to treat the indicated disease, disorder or condition. The methodsas herein described each and/or all may further comprise administrationof an additional therapeutic agent as herein described, and as will beappreciated by one skilled in the art.

In some embodiments, the present invention provides a method forenhanced production such as milk, sperm, or egg. In some embodiments,the present invention provides a method for enhanced production of leanmeats or eggs. In some embodiments, the present invention provides amethod for increased productivity of feeds or stud livestock, forexample, increased sperm count, improved morphology of sperm, etc. Insome embodiments, the present invention provides a method for expandingthe productive life of farm animals, for example, egg-laying hens,milk-producing cows, etc, and/or enhanced herd health, for example,improved immune clearance, stronger animals.

In one embodiment, the method comprises administering to a subject acomposition comprising a compound of this invention and an anti-canceragent, an immunomodulating agent, an antidiabetic agent, an agenttreating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins,nutritional additives, hormones, each and/or all as herein described, orany other therapeutic agent as herein described, or a combinationthereof.

In another embodiment, this invention provides methods of treatment ofcystic fibrosis and induced hypogonadal states as a result of the same,epilepsy and induced hypogonadal and/or hypermetabolic states as aresult of the same, hereditary angioedema, lupus erythematosus anddecreased BMD as a result of the same, alcohol and smoking inducedosteoporosis, in a subject the methods comprising administering a SARMas herein described to the subject.

In another embodiment, this invention provides methods of treatment ofpolio and post-polio syndrome and other invalid states, statin inducedrhabdomyolysis, statin-induced muscle weakness, statin-induced organfailure or insufficiency, in a subject, the methods comprising theadministration of a compound as herein described, optionally with astatin, as appropriate, as will be appreciated by one skilled in theart, and/or with any therapeutic agent.

In another embodiment, this invention provides a method of treatingOpioid Induced Androgen Deficiency (OPIAD), the method comprisingadministering to the subject a compound as herein described, andoptionally opiates, opioids, narcotics, etc. methadone, long-actingopiates/opioids such as Kadian, extended release morphines, allopiates/opioids/narcotics agents approved by FDA, opiates/opioids usedin treatment of heroin addiction, opiates/opioids used in the treatmentof chronic pain of malignancy, opiates/opioids used in the treatmentnon-malignant of chronic pain syndromes.

In another embodiment, this invention provides a method of treating anervous system disease, disorder or condition, the method comprisingadministering to the subject a compound as herein described, andoptionally anti-psychotics, such as, for example, zotepine, haloperidol,amisulpride, risperidone, other D2 dopamine receptor antagonists;anti-epileptics, such as valproic acid, carbamazepine, oxcarbamazepine,etc. or combinations thereof.

In another embodiment, this invention provides a method of treating ahormone dependent disease, disorder or condition, the method comprisingadministering to the subject a compound as herein described, andoptionally chemotherapeutics agents and therapies (methotrexate,cyclophosphamide, ifosfamide, adriamycin, doxorubicin, glucocorticoids,cyclosporine, L-thyroxine, SERMs, AI, fulvestrant, GnRH agents, ADT,discontinuation of hormone replacement therapy, cranial irradiation,peripheral irradiation, etc.; prolactinemia-inducingpharmacotherapeutics (serotonergic antidepressants acting through 5HT2receptors, selective serotonin reuptake inhibitors, monoamine oxidaseinhibitors, tricyclic antidepressants, antihypertensives such asmethyldopa, reserpine, clonidine, and verapamil; antidopaminergicanti-emetics such as metoclopramide, H2 receptor antagonists such ascimetidine and ranitidine, estrogens, amphetamines, AR partialantagonists (ketoconazole, spironolactone, eplerenone)

In another embodiment, the compounds of this invention and compositionsas described herein are useful in promoting or speeding recoveryfollowing a surgical procedure.

In one embodiment, the present invention provides a use of a compound asdescribed herein for reducing a fat mass in a subject. In anotherembodiment the invention provides such methods for use of the compoundas described herein or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, or a composition comprising the same.

In another embodiment, this invention provides for the use of a compoundas described herein or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, or a composition comprising the same, in treating abdominal fataccumulation; improving body composition; lowering body fat content;lowering fat mass; improving blood lipid profile, increasing musclemass/strength/function; increasing bone mass/BMD/strength/function;lowering body fat; congenital hyperinsulinemia; cushing's disease(hypercortisolemia); obesity or diabetes associated with a metabolicsyndrome in a subject.

In another embodiment, the subject has a hormonal imbalance, disorder,or disease. In another embodiment the subject has menopause.

In one embodiment, the present invention provides a use of a compound asdescribed herein for increasing a lean mass in a subject. In anotherembodiment such use comprises administration of a compound as describedherein or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof.

In one embodiment the subject has a hormonal imbalance, disorder, ordisease. In another embodiment the subject has menopause.

Example 4 demonstrates that a compound of formula (II) is anabolic yetminimally androgenic, thus such compounds may be useful in treatingpatient groups in which androgens were contraindicated in the past.Compound of formula (II) was shown to stimulate muscle growth, whetherin the presence or absence of testosterone while exertinganti-proliferative effects on the prostate, thus, in one embodiment, themethods of this invention provide for restoring lost muscle mass inpatients with sarcopenia or cachexia.

In one embodiment, the compounds as herein described alter the levels ofleptin in a subject. In another embodiment, the compounds as hereindescribed decrease the levels of leptin. In another embodiment, thecompounds as herein described increase the levels of leptin in asubject. Leptin is known to have an effect on appetite on weight loss inobese mice, and thus has been implicated in obesity.

The compounds as herein described, in one embodiment, affectcirculating, or in another embodiment, tissue levels of leptin. In oneembodiment, the term ‘level/s of leptin’ refers to the serum level ofleptin. As contemplated herein, the compounds of the present inventionhave an effect on leptin in-vitro and in-vivo. Leptin levels can bemeasured by methods known to one skilled in the art, for example bycommercially available ELISA kits. In addition, Leptin levels may bedetermined in in-vitro assays, or in in-vivo assays, by any method knownto a person skilled in the art.

Since leptin is implicated in controlling appetite, weight loss, foodintake, and energy expenditure, modulating and/or controlling the levelsof leptin is a useful therapeutic approach in treating preventing,inhibiting or reducing the incidence of obesity in subjects sufferingfrom obesity. Modulating the level of leptin can result in a loss ofappetite, a reduction of food intake, and an increase in energyexpenditure in the subject, and thus may contribute to the control andtreatment of obesity.

The term “obesity” is defined, in one embodiment, as an increase in bodyweight beyond the limitation of skeletal and physical requirement, asthe result of excessive accumulation of fat in the body.

The term “obesity-associated metabolic disorder” refers, in oneembodiment, to a disorder which results from, is a consequence of, isexacerbated by or is secondary to obesity. Non-limiting examples of sucha disorder are osteoarthritis, Type II diabetes mellitus, increasedblood pressure, stroke, and heart disease.

Cholesterol, triacylglycerol and other lipids are transported in bodyfluids by lipoproteins which may be classified according to theirdensity, for example, the very low density lipoproteins (VLDL),intermediate density lipoproteins (HDL), low density lipoproteins (LDL)and high density lipoproteins (HDL).

It has been shown that high levels of LDL-Cholesterol in the bloodcorrelate with atherosclerosis which is a progressive diseasecharacterized in part by sedimentation of lipids in inner walls ofarteries, particularly of coronary arteries. It has also been shown thata high blood level of LDL-Cholesterol correlates with coronary heartdisease. Also, a negative correlation exists between blood levels of HDLcholesterol and coronary heart disease.

The level of total cholesterol in blood, which is the sum ofHDL-Cholesterol, LDL-Cholesterol, VLDL-Cholesterol andchylomicron-Cholesterol, is not necessarily predictive of the risk ofcoronary heart disease and atherosclerosis.

The correlation between atherosclerosis and LDL cholesterol levels,however, is much higher than a similar correlation betweenatherosclerosis and total serum cholesterol levels.

In one embodiment, this invention provides methods of use of thecompounds as herein described for improving the lipid profile and/orreducing the circulating lipid levels in a subject. In some embodiments,according to this aspect of the invention, the subject suffers from oneor more conditions selected from the group consisting of:atherosclerosis and its associated diseases, premature aging,Alzheimer's disease, stroke, toxic hepatitis, viral hepatitis,peripheral vascular insufficiency, renal disease, and hyperglycemia, andthe invention provides for the administration of a compound orcomposition comprising the same, as herein described, which in someembodiments positively affects a lipid profile in the subject, which isone means by which the method is useful in treating the indicateddiseases, disorders and conditions.

In one embodiment the invention provides for the treatment ofatherosclerosis and its associated diseases, such as for example,cardiovascular disorders, cerebrovascular disorders, peripheral vasculardisorders, intestinal vascular disorders, or combinations thereof.

In one embodiment cardiovascular disorders comprise of hypertention(HTN), coronary artery disease (CAD) or myocardial perfusion. In anotherembodiment this invention provides methods of use of the SARM compoundsas herein described for promoting aortic smooth muscle cellproliferation. In another embodiment this invention provides methods ofuse of the compounds as herein described for treating arteriosclerosis.In another embodiment this invention provides methods of use of thecompounds as herein described for lowering blood pressure. In anotherembodiment this invention provides methods of use of the compounds asherein described for treating cardiac diseases and disorders comprisingcardiomyopathy, cardiac dysfunctions such as, myocardial infarction,cardiac hypertrophy and cognitive heart failure. In another embodimentthis invention provides methods of use of the compounds as hereindescribed for cardioprotection comprising cardioprotection in insulinresistance; treating diabetes type I and II, metabolic syndrome,syndrome X and/or high blood pressure.

In one embodiment, the invention provides a method of treating,preventing, reducing the risk of mortality from cardiovascular and/orcerebrovascular disease in a subject, comprising administering acompound of this invention or its prodrug, ester, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, hydrate or anycombination thereof, or a pharmaceutical composition comprising thesame. In one embodiment, the compound is characterized by the structureof formula (II).

In one embodiment, compounds of this invention reduce LDL and totalcholesterol levels. In another embodiment the compound of formula (II)reduces LDL and total cholesterol levels in a subject. In oneembodiment, the compound is characterized by the structure of theformula I-XXII, or any embodiment thereof, as herein described.

In another embodiment, compounds of formulae I are co-administered withHDL-elevating agents. In another embodiment, a compound of thisinvention is co-administered with an HDL-elevating agents. In anotherembodiment, HDL-elevating agents include niacin. In another embodimentthe HDL-elevating agents include fibrates including gemfibrozil (Lopid),thiourea based gemfibrozil analogues, and fenofibrate (TriCor). Inanother embodiment, HDL-elevating agents include statins. In anotherembodiment, HDL-elevating agents include1-hydroxyalkyl-3-phenylthiourea, and analogs thereof.

In one embodiment, this invention provides a method of reducingcirculating lipid levels in a subject, said method comprisingadministering a compound of this invention or its pharmaceuticallyacceptable salt, hydrate, N-oxide, or any combination thereof, or acomposition comprising the same. In one embodiment, the subject suffersfrom atherosclerosis and its associated diseases, premature aging,Alzheimer's disease, stroke, toxic hepatitis, viral hepatitis,peripheral vascular insufficiency, renal disease, hyperglycemia, or anycombination thereof. In one embodiment, the compound is characterized bythe structure of the formula I-XXII, or any embodiment thereof, asherein described.

In one embodiment, this invention provides a method of treatingatherosclerosis and its associated diseases, such as, for example,cardiovascular disorders, cerebrovascular disorders, peripheral vasculardisorders, or intestinal vascular disorders in a subject, the methodcomprising the step of administering to the subject compound of thisinvention or its pharmaceutically acceptable salt, hydrate, N-oxide, orany combination thereof, or a composition comprising the same. In oneembodiment, the compound is characterized by the structure of theformula I-XXII, or any embodiment thereof, as herein described.

The method may further comprise co-administration, subsequent or prioradministration with an agent or agents, which are known to be useful intreating cardiovascular disorders, cerebrovascular disorders, peripheralvascular disorders, or intestinal vascular disorders.

In one embodiment, this invention provides a method of improving thedexterity and movement in a subject, for example, by treating arthritisin the subject.

The term “arthritis” refers, in another embodiment, to anon-inflammatory degenerative joint disease occurring chiefly in olderpeople, characterized by degeneration of the articular cartilage,hypertrophy of bones and the margins, changes in the synovial membrane,etc. It is accompanied, in other embodiments, by pain and stiffness,particularly after prolonged activity.

The term “diabetes”, in one embodiment, refers to a relative or absolutelack of insulin leading to uncontrolled carbohydrate metabolism. Mostpatients can be clinically classified as having either insulin-dependentdiabetes mellitus (IDDM or Type-I diabetes) or non-insulin-dependentdiabetes mellitus (NIDDM or Type-II diabetes).

The term “increased blood pressure” or “hypertension” refers, in otherembodiments, to a repeatedly high blood pressure above 140 over 90 mmHg.Chronically-elevated blood pressure can cause blood vessel changes inthe back of the eye, thickening of the heart muscle, kidney failure, andbrain damage.

The term “stroke” refers, in other embodiments, to damage to nerve cellsin the brain due to insufficient blood supply often caused by a burstingblood vessel or a blood clot. The term “heart disease”, in otherembodiments, refers to a malfunction in the heart normal function andactivity, including heart failure.

In addition, androgens have recently been shown to be involved incommitment of mesenchymal pluripotent cells into myogenic lineage and toblock differentiation into adipogenic lineage (Singh et al.,Endocrinology, 2003, Jul 24). Accordingly, the compounds can be usefulin methods of blocking adipogenesis, and/or altering stem celldifferentiation, as described herein.

In another embodiment, this invention relates to a method of promoting,increasing or facilitating weight loss in a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to promote,increase or facilitate weight loss in the subject.

In another embodiment, this invention relates to a method of decreasing,suppressing, inhibiting or reducing appetite of a subject, comprisingthe step of administering to the subject a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal, or any combination thereof, in an amount effectiveto decrease, suppress, inhibit or reduce the appetite of the subject.

In another embodiment, this invention relates to a method of alteringthe body composition of a subject, comprising the step of administeringto the subject a compound as herein described and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal,or any combination thereof, in an amount effective to alter the bodycomposition of the subject. In one embodiment, altering the bodycomposition comprises altering the lean body mass, the fat free bodymass of the subject, or a combination thereof.

In another embodiment, this invention relates to a method of alteringlean body mass or fat free body mass of a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to alter thelean body mass or fat free body mass of the subject.

In another embodiment, this invention relates to a method of convertingfat to lean muscle in a subject, comprising the step of administering tothe subject a compound as herein described and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal,or any combination thereof, in an amount effective to convert fat tolean muscle in the subject.

In another embodiment, this invention relates to a method of treating anobesity-associated metabolic disorder in a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to treat theobesity-associated metabolic disorder in the subject.

In another embodiment, this invention relates to a method of preventing,suppressing, inhibiting or reducing an obesity-associated metabolicdisorder in a subject, comprising the step of administering to thesubject a compound as herein described and/or its analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, prodrug, polymorph, crystal, or anycombination thereof, in an amount effective to prevent, suppress,inhibit or reduce the obesity-associated metabolic disorder in thesubject.

In one embodiment, the obesity-associated metabolic disorder ishypertension. In another embodiment, the disorder is osteoarthritis. Inanother embodiment, the disorder is Type II diabetes mellitus. Inanother embodiment, the disorder is increased blood pressure. In anotherembodiment, the disorder is stroke. In another embodiment, the disorderis heart disease.

In another embodiment, this invention relates to a method of decreasing,suppressing, inhibiting or reducing adipogenesis in a subject,comprising the step of administering to the subject a compound as hereindescribed and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal, or any combination thereof.

In another embodiment, this invention relates to a method of alteringstem cell differentiation in a subject, comprising the step ofadministering to the subject a compound as herein described and/or itsanalog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to alterstem cell differentiation in the subject.

In one embodiment, the compounds as herein described are useful in a)treating, preventing, suppressing, inhibiting, or reducing obesity; b)promoting, increasing or facilitating weight loss; c) decreasing,suppressing, inhibiting or reducing appetite; d) altering the bodycomposition; e) altering lean body mass or fat free body mass; f)converting fat to lean muscle; g) treating, preventing, suppressing,inhibiting, or reducing an obesity-associated metabolic disorder, forexample hypertension, osteoarthritis, diabetes mellitus, MODY, increasedblood pressure, stroke, or heart disease; h) decreasing, suppressing,inhibiting or reducing adipogenesis; i) altering stem celldifferentiation; and/or j) altering the level of leptin.

In one embodiment, the compounds as herein described find utility intreating or halting the progression of, or treating symptoms ofdiabetes. In another embodiment, the compounds as herein described areuseful in treating co-morbidities related to diabetes. These conditionsinclude: hypertension (HTN), cerebrovascular disease, atheroscleroticcoronary artery disease, macular degeneration, diabetic retinopathy (eyedisease) and blindness, cataracts—systemic inflammation (characterizedby elevation of inflammatory markers such as erythrocyte sedimentationrate or C-reactive protein), birth defects, pregnancy related diabetes,pre-ecclampsia and hypertension in pregnancy, kidney disease (renalinsufficiency, renal failure etc.), nerve disease (diabetic neuropathy),superficial and systemic fungal infections, congestive heart failure,gout/hyperuricemia, obesity, hypertriglyceridemia, hypercholesterolemia,fatty liver disease (non-alcoholic steatohepatitis, or NASH), anddiabetes-related skin diseases' such as Necrobiosis LipoidicaDiabeticorum (NLD), Blisters of diabetes (Bullosis Diabeticorum),Eruptive Xanthomatosis, Digital Sclerosis, Disseminated GranulomaAnnulare, and Acanthosis Nigricans.

In one embodiment this invention provides a method of treating,suppressing, inhibiting or reducing the incidence of (a) diabetes typeI; (b) diabetes type II; (c) glucose intolerance; (d) hyperinsulinemia;(e) insulin resistance (f) nephropathy; (g) diabetic neuropathy; (h)diabetic retinopathy (i) fatty liver conditions (j) MODY and (k)cardiovascular disease in a human subject, comprising the step ofadministering to said subject a compound of this invention. In oneembodiment, the compound is characterized by the structure of theformula I-XXII, or any embodiment thereof, as herein described.

In some embodiments, the compounds as herein described and/orcompositions comprising the same may be used for applications in, ortreating diseases or conditions associated with a subject havingdiabetes. In one embodiment, the subject for whom treatment is soughtvia the methods of this invention is one with diabetic I. Type Idiabetes is characterized by autoimmune destruction of pancreaticbeta-cells. Markers of immune destruction of the beta-cell are presentat the time of diagnosis in 90% of individuals and include antibodies tothe islet cell (ICAs), to glutamic acid decarboxylase (GAD), and toinsulin (IAAs). While this form of diabetes usually occurs in childrenand adolescents, it can occur at any age. Younger individuals typicallyhave a rapid rate of beta-cell destruction and present withketoacidosis, while adults often maintain sufficient insulin secretionto prevent ketoacidosis for many years. Eventually, all type I diabeticpatients require insulin therapy to maintain normglycemia.

In one embodiment, this invention provides a method of treating diabetestype II. Type II diabetes is characterized by insulin resistance and atsome stage in pathogenesis of the disease, a relative deficiency ofinsulin secretion. In absolute terms, the plasma insulin concentration(both fasting and meal-stimulated) usually is increased, although“relative” to the severity of insulin resistance, the plasma insulinconcentration is insufficient to maintain normal glucose homeostasis.With time, however, there is progressive beta cell failure and absoluteinsulin deficiency ensues. Most individuals with type II diabetesexhibit intra abdominal (visceral) obesity, fatty liver, which isclosely related to the presence of insulin resistance. The patient'sliver becomes insulin resistant and glycogen breakdown is uncontrolledand the result is increased and unphysiological glucose delivery to thebloodstream. The liver generated cholesterol and VLDL particles is alsouncontrolled. In addition, hypertension, dyslipidemia (high triglycerideand low HDL-cholesterol levels; postprandial hyperlipemia), and elevatedPAI-1 levels often are present in these individuals. This clustering ofabnormalities is referred to as the “insulin resistance syndrome”, orthe “metabolic syndrome” or obesity related disorders. Because of theseabnormalities, patients with type II diabetes are at increased risk ofdeveloping macrovascular complications such as myocardial infarction andstroke.

In one embodiment, this invention provides a method of treating diabeticnephropathy. Diabetic nephropathy is a complication of diabetes thatevolves early, typically before clinical diagnosis of diabetes is made.The earliest clinical evidence of nephropathy is the appearance of lowbut abnormal levels (>30 mg/day or 20 μg/min) of albumin in the urine(microalbuminuria), followed by albuminuria (>300 mg/24 h or 200 μg/min)that develops over a period of 10-15 years. In patients with type 1diabetes, diabetic hypertension typically becomes manifest early on, bythe time that patients develop microalbuminuria. Once overt nephropathyoccurs, the glomerular filtration rate (GFR) falls over a course oftimes, which may be several years, resulting in End Stage Renal Disease(ESRD) in diabetic individuals.

In one embodiment, this invention provides a method of treating diabeticneuropathy. Diabetic neuropathy is a family of nerve disorders caused bydiabetes. Diabetic neuropathies cause numbness and sometimes pain andweakness in the hands, arms, feet, and legs. Neurologic problems indiabetes may occur in every organ system, including the digestive tract,heart, and genitalia. Diabetic neuropathies are classified asperipheral, autonomic, proximal, and focal. Peripheral neuropathy causespain or loss of feeling in the toes, feet, legs, hands, and arms.Autonomic neuropathy causes changes in digestion, bowel and bladderfunction, sexual response, and perspiration and can also affect thenerves that serve the heart and control blood pressure. Proximalneuropathy causes pain in the thighs, hips, or buttocks and leads toweakness in the legs. Focal neuropathy results in the sudden weakness ofone nerve, or a group of nerves, causing muscle weakness or pain. Anynerve in the body may be affected.

In one embodiment, this invention provides a method of treating diabeticretinopathy. The effect of diabetes on the eye is called diabeticretinopathy. Patients with diabetes are more likely to develop eyeproblems such as cataracts and glaucoma. The affect of diabeticretinopathy on vision varies widely, depending on the stage of thedisease. Some common symptoms of diabetic retinopathy are blurred vision(this is often linked to blood sugar levels), floaters and flashes andsudden loss of vision.

In one embodiment, the subject for whom treatment is sought via themethods of this invention is one with glucose intolerance. Glucoseintolerance is a pre-diabetic state in which the blood glucose is higherthan normal but not high enough to warrant the diagnosis of diabetes.

In one embodiment, the subject for whom treatment is sought via themethods of this invention is one with hyperinsulinemia. Hyperinsulinemiais a sign of an underlying problem that is causing the pancreas tosecrete excessive amounts of insulin. The most common cause ofhyperinsulinemia is insulin resistance, a condition in which your bodyis resistant to the effects of insulin and the pancreas tries tocompensate by making more insulin. hyperinsulinemia is associated withtype II diabetes

In one embodiment, the subject for whom treatment is sought via themethods of this invention is one with insulin resistance. Insulinresistance is a condition in which normal amounts of insulin areinadequate to produce a normal insulin response from fat, muscle andliver cells. Insulin resistance in fat cells results in hydrolysis ofstored triglycerides, which elevates free fatty acids in the bloodplasma. Insulin resistance in muscle reduces glucose uptake whereasinsulin resistance in liver reduces glucose storage, with both effectsserving to elevate blood glucose. High plasma levels of insulin andglucose due to insulin resistance often leads to the metabolic syndromeand type It diabetes.

Diabetes and the liver obesity is typically associated with elevatedlevels of free fatty acid (FFAs) that promote lipid accumulation andinsulin resistance in target tissues, i.e. reduced action of insulinprimarily in skeletal muscle and liver. A prominent role of insulin isto reduce glucose output from the liver. FFAs stimulate hepaticgluconeogenesis which per se does not lead to increased hepatic glucoseoutput as long as it is paralleled by a decrease in hepaticglycogenolysis, a compensatory process referred to as “hepaticautoregulation”. FFAs stimulate insulin secretion and insulin blocksglycogenolysis in part by inhibiting secretion of glucagon, an inducerof glycogenolysis. However, long-term elevated levels of FFAs leads tohepatic insulin resistance and thus breakdown of hepatic autoregulation,resulting in increased hepatic glucose production and development oftype II diabetes. Fatty liver and hepatic insulin resistance is a majordriving force behind hyperglycemia and type II diabetes.

In one embodiment, this invention provides methods that inhibit(improve) the fatty liver, resulting in that the insulin resistance inthe liver is inhibited (improved) and thereby solving the basic problemin type II diabetes.

In another embodiment, the diabetes is a type I diabetes. In anotherembodiment, the diabetes is a type II diabetes.

In one embodiment, this invention provides a method of treatingsuppressing, inhibiting or reducing the incidence of diabetes is a humansubject, comprising the step of administering to said subject a compoundof this invention or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, or any combination thereof. Inone embodiment, the compound is characterized by the structure of theformula I-XXII, or any embodiment thereof, as herein described.

In another embodiment, the diabetes is a Type I diabetes. In anotherembodiment, the diabetes is a type II diabetes.

In one embodiment, this invention provides a method of treating a humansubject having glucose intolerance, comprising the step of administeringto said subject compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or any combination thereof. In one embodiment, the compound ischaracterized by the structure of the formula I-XXII, or any embodimentthereof, as herein described.

In one embodiment, this invention provides a method of treatinghyperinsulinemia in a human subject, comprising the step ofadministering to said subject a compound of this invention or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, or any combination thereof.

In one embodiment, the compound is characterized by the structure of theformula I-XXII, or any embodiment thereof, as herein described.

In one embodiment, this invention provides a method of treating insulinresistance in a human subject, comprising the step of administering tosaid subject the compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or any combination thereof. In one embodiment, the compound ischaracterized by the structure of the formula I-XXII, or any embodimentthereof, as herein described.

In one embodiment, this invention provides a method of treating diabeticnephropathy in a human subject, comprising the step of administering tosaid subject a selective androgen receptor modulator compound of thisinvention or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, or any combination thereof. Inone embodiment, the compound is characterized by the structure of theformula I-XXII, or any embodiment thereof, as herein described.

In one embodiment, this invention provides a method of treating diabeticneuropathy in a human subject, comprising the step of administering tosaid subject compound of this invention or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, or anycombination thereof. In one embodiment, the compound is characterized bythe structure of the formula I-XXII, or any embodiment thereof, asherein described.

In one embodiment, this invention provides a method of treating diabeticretinopathy in a human subject, comprising the step of administering tosaid subject a compound of this invention or its isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or any combination thereof. In one embodiment, the compound ischaracterized by the structure of the formula I-XXII, or any embodimentthereof, as herein described.

In one embodiment, this invention provides a method of treating fattyliver conditions in a human subject, comprising the step ofadministering to said subject a selective androgen receptor modulatorcompound of this invention or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, or any combinationthereof. In one embodiment, the compound is characterized by thestructure of the formula I-XXII, or any embodiment thereof, as hereindescribed.

In one embodiment, this invention provides a method of treatingovascular disease in a human subject, comprising the step ofadministering to said subject a compound of this invention or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, or any combination thereof.

In one embodiment, the compound is characterized by the structure of theformula I-XXII, or any embodiment thereof, as herein described.

In one embodiment this invention provides a method for a) treating,preventing, suppressing inhibiting atherosclerosis b) treating,preventing, suppressing inhibiting liver damage due to fat depositscomprising the step of administering to the subject a compound asdescribed herein and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal, or any combination thereof, or acomposition comprising the same, in an amount effective to treat,prevent or inhibit atherosclerosis and liver damage due to fat deposit.

In one embodiment, the compound as described herein is useful in a)treating, preventing, suppressing, inhibiting, or reducingatherosclerosis; b) treating, preventing, suppressing inhibiting liverdamage due to fat deposits.

In one embodiment atherosclerosis refers to a slow, complex disease thatmay begin with damage to the innermost layer of the artery. In anotherembodiment the causes of damage to the arterial wall may include a)elevated levels of cholesterol and in the blood; b) high blood pressure;c) tobacco smoke d) diabetes. In another embodiment, the condition istreatable in a smoker, despite the fact that tobacco smoke may greatlyworsen atherosclerosis and speed its growth in the coronary arteries,the aorta and arteries in the legs. Similarly, in another embodiment,the methods of this invention may be useful in treating subjects with afamily history of premature cardiovascular disease who have an increasedrisk of atherosclerosis.

In one embodiment, liver damage due to fat deposits refer to thebuild-up of fat in the liver cells forming a Fatty Liver which may beassociated with or may lead to inflammation of the liver. This can causescarring and hardening of the liver. When scarring becomes extensive, itis called cirrhosis.

In another embodiment the fat accumulates in the liver as obesity. Inanother embodiment fatty liver is also associated with diabetesmellitus, high blood triglycerides, and the heavy use of alcohol. Inanother embodiment fatty Liver may occur with certain illnesses such astuberculosis and malnutrition, intestinal bypass surgery for obesity,excess vitamin A in the body, or the use of certain drugs such asvalproic acid (trade names: Depakene/Depakote) and corticosteroids(cortisone, prednisone). Sometimes fatty liver occurs as a complicationof pregnancy.

In one embodiment, subjects with kidney disease, in particular malesubjects with end-stage renal disease (ESRD) suffer from hypogonadism,with some having concomitant moderate to severe protein-energymalnutrition (PEM), which leads to higher required doses of EPO, lowerQOL scores, and higher mortality. Many have other symptoms associatedwith hypogonadism, including fatigue, lack of apetite, muscle weakness,etc. In some embodiments, the treatment methods of this invention areuseful in treating symptoms associated with hypogonadism, brought aboutin the subject by the kidney disease or disorder.

In one embodiment, diabetic nephropathy is a complication of diabetesthat evolves early, typically before clinical diagnosis of diabetes ismade. The earliest clinical evidence of nephropathy is the appearance oflow but abnormal levels (>30 mg/day or 20 μg/min) of albumin in theurine (microalbuminuria), followed by albuminuria (>300 mg/24 h or 200μg/min) that develops over a period of 10-15 years. In patients withtype 1 diabetes, diabetic hypertension typically becomes manifest earlyon, by the time that patients develop microalbuminuria. Once overtnephropathy occurs, the glomerular filtration rate (GFR) falls over acourse of times, which may be several years, resulting in End StageRenal Disease (ESRD) in diabetic individuals.

Hypertension is another comorbid factor for renal disease. In someembodiments, treatment of renal disease according to the presentinvention may comprise concomitant treatment with a compound of thisinvention and an agent which treats hypertension.

Androgen-dependent conditions which may be treated with the compoundsand/or compositions as herein described, comprising the methods of thepresent invention include those conditions which are associated withaging. In one embodiment, the compound as described herein is useful ina) Age-related functional decline (ARFD); b) reversal or prevention ofARFD; c) reversal or prevention of ARFD in elderly d) reversal orprevention of ARFD-induced sarcopenia or osteopenia; e) Andropause,andropausal vasomotor symptoms, f) andropausal gynecomastia, musclestrength/function; g) bone strength/function; h) Anger; i) Asthenia; j)Chronic fatigue syndrome; k) Cognitive impairment; and/or l) improvingcognitive function.

In one embodiment, the compound as described herein is useful intreating inflammation and related disorders such as:a) prevention,treatment, or reversal of arthritis; b) prevention, treatment, orreveral of an arthritic condition such as Behcet's disease (autoimmunevasculitis), bursitis, calcium pyrophosphate dihydrate crystal (CPPD),deposition disease (or pseudogout), carpal tunnel syndrome, connectivetissue disorders, Crohn's disease, Ehlers-Danlos syndrome (EDS),fibromyalgia, gout, infectious arthritis, inflammatory bowel disease(IBD), juvenile arthritis, systemic lupus erythematosus (SLE), Lyme'sdisease, Marfan syndrome, myositis, osteoarthritis, polyarteritisnodosa, polymyalgia rheumatica, psoriasis, psoriatic arthritis,Raynaud's phenomenon, reflex sympathetic dystrophy syndrome, Reiter'ssyndrome, rheumatoid arthritis, scleroderma, Sjögrens' syndrome,tendonitis or ulcerative colitis; c) preventing, treatment, or reversingan autoimmune disease.

In one embodiment, the compound as described herein is useful inprevention of iatrogenic effects comprising acute fatigue syndrome(post-surgical) or androgen-deprivation therapy (ADT) induced sideeffects such as reduced muscle mass, reduced muscle strength, frailty,hypogonadism, osteoporosis, osteopenia, decreased BMD and/or decreasedbone mass.

In one embodiment, the compounds and/or compositions and/or methods ofuse thereof are for the treatment of human subjects, wherein, in oneembodiment, the subject is male, or in another embodiment, the subjectis female.

In one embodiment, the methods of the present invention compriseadministering a compound of this invention as the sole activeingredient. However, also encompassed within the scope of the presentinvention are methods for diabetes and related disorders, hormonetherapy, dry eye, obesity, treating prostate cancer, delaying theprogression of prostate cancer, and for preventing and/or treating therecurrence of prostate cancer, male contraception; treatment ofosteoporosis, treatment of conditions associated with ADIF and fortreatment and/or prevention of chronic muscular wasting which compriseadministering the compounds in combination with one or more therapeuticagents. These agents include, but are not limited to: LHRH analogs,reversible antiandrogens, antiestrogens, anticancer drugs, 5-alphareductase inhibitors, aromatase inhibitors, progestins, agents actingthrough other nuclear hormone receptors, selective estrogen receptormodulators (SERM), progesterone, estrogen, PDE5 inhibitors, apomorphine,bisphosphonate, and one or more additional SARMs.

Thus, in one embodiment, the methods of the present invention compriseadministering the compound of this invention in combination withdiabetes drug such as Troglitazone, Rosiglitazone, and Pioglitazone. Inanother embodiment, the methods of the present invention compriseadministering the compound in combination with an LHRH analog. Inanother embodiment, the methods of the present invention compriseadministering the compound, in combination with a reversibleantiandrogen. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with anantiestrogen. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with ananticancer drug. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with a5-alpha reductase inhibitor. In another embodiment, the methods of thepresent invention comprise administering the compound, in combinationwith an aromatase inhibitor. In another embodiment, the methods of thepresent invention comprise administering the compound, in combinationwith a progestin. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with anagent acting through other nuclear hormone receptors. In anotherembodiment, the methods of the present invention comprise administeringthe compound, in combination with a selective estrogen receptormodulators (SERM). In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with aprogesterone. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with anestrogen. In another embodiment, the methods of the present inventioncomprise administering the compound, in combination with a PDE5inhibitor. In another embodiment, the methods of the present inventioncomprise administering the compound, in combination with apomorphine. Inanother embodiment, the methods of the present invention compriseadministering the compound, in combination with a bisphosphonate. Inanother embodiment, the methods of the present invention compriseadministering the compound, in combination with one or more additionalSARMs. In some embodiments, the methods of the present inventioncomprise combined preparations comprising the compound and an agent asdescribed hereinabove. In some embodiments, the combined preparationscan be varied, e.g., in order to cope with the needs of a patientsubpopulation to be treated or the needs of the single patient whichdifferent needs can be due to the particular disease, severity of thedisease, age, sex, or body weight as can be readily determined by aperson skilled in the art. In some embodiments, the methods of thepresent invention comprise personalized medicine methods which treat theneeds of a single patient. In one embodiment, different needs can be dueto the particular disease, severity of the disease, the overall medicalstate of a patient, or the age of the patient. In some embodiments,personalized medicine is the application of genomic data to bettertarget the delivery of medical interventions. Methods of personalizedmedicine, in some embodiments, serve as a tool in the discovery andclinical testing of new products of the present invention. In oneembodiment, personalized medicine involves the application of clinicallyuseful diagnostic tools that may help determine a patient'spredisposition to a particular disease or condition. In someembodiments, personalized medicine is a comprehensive approach utilizingmolecular analysis of both patients and healthy individuals to guidedecisions throughout all stages of the discovery and development ofpharmaceuticals and diagnostics; and applying this knowledge in clinicalpractice for a more efficient delivery of accurate and qualityhealthcare through improved prevention, diagnosis, treatment, andmonitoring methods.

It is to be understood that any use of any of the compounds as hereindescribed may be used in the treatment of any disease, disorder orcondition as described herein, and represents an embodiment of thisinvention.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES Example 1 Synthesis of (S) Enantiomer of Compound of Formula II

(2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid. D-Proline, 14.93 g,0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath;the resulting alkaline solution was diluted with acetone (71 mL). Anacetone solution (71 mL) of metacryloly chloride (13.56 g, 0.13 mol) and2N NaOH solution (71 mL) were simultaneously added over 40 min to theaqueous solution of D-proline in an ice bath. The pH of the mixture waskept at 10-11° C. during the addition of the metacryloly chloride. Afterstirring (3 h, room temperature), the mixture was evaporated in vacuo ata temperature at 35-45° C. to remove acetone. The resulting solution waswashed with ethyl ether and was acidified to pH 2 with concentrated HCl.The acidic mixture was saturated with NaCl and was extracted with EtOAc(100 mL×3). The combined extracts were dried over Na₂SO₄, filteredthrough Celite, and evaporated in vacuo to give the crude product as acolorless oil. Recrystallization of the oil from ethyl ether and hexanesafforded 16.2 (68%) of the desired compound as colorless crystals: mp102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of thiscompound demonstrated the existence of two rotamers of the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ 5.28 (s) and 5.15 (s) for thefirst rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2Hfor both rotamers, vinyl CH₂), 4.48-4.44 for the first rotamer,4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CHat the chiral canter), 3.57-3.38 (m, 2H, CH₂), 2.27-2.12 (1H, CH),1.97-1.72 (m, 6H, CH₂, CH, Me); ¹³C NMR (75 MHz, DMSO-d₆) 8 for majorrotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: forminor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7;IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369,1348, 1178 cm⁻¹; [α]_(D) ²⁶+80.8° (c=1, MeOH); Anal. Calcd. forC₉H₁₃NO₃: C, 59.00; H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N, 7.61.

(3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo[2,1-c][1,4]oxazine-1,4-dione.A solution of NBS (23.5 g, 0.132 mol) in 100 mL of DMF was addeddropwise to a stirred solution of the (methyl-acryloyl)-pyrrolidine(16.1 g, 88 mmol) in 70 mL of DMF under argon at room temperature, andthe resulting mixture was stirred 3 days. The solvent was removed invacuo, and a yellow solid was precipitated. The solid was suspended inwater, stirred overnight at room temperature, filtered, and dried togive 18.6 (81%) (smaller weight when dried ˜34%) of the title compoundas a yellow solid: mp 152-154° C. (lit. [214] mp 107-109° C. for theS-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H,CH at the chiral center), 4.02 (d, J=11.4 Hz, 1H, CHH_(a)), 3.86 (d,J=11.4 Hz, 1H, CHH_(b)), 3.53-3.24 (m, 4H, CH₂), 2.30-2.20 (m, 1H, CH),2.04-1.72 (m, 3H, CH₂ and CH), 1.56 (s, 2H, Me); ¹³C NMR (75 MHz,DMSO-d₆) δ 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR(KBr) 3474, 1745 (C═O), 1687 (C═O), 1448, 1377, 1360, 1308, 1227, 1159,1062 cm⁻¹; [α]_(D) ²⁶+124.5° (c=1.3, chloroform); Anal. Calcd. forC₉H₁₂BrNO₃: C, 41.24; H, 4.61; N, 5.34. Found: C 41.46, H 4.64, N 5.32.

(2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid. A mixture of bromolactone(18.5 g, 71 mmol) in 300 mL of 24% HBr was heated at reflux for 1 h. Theresulting solution was diluted with brine (200 mL), and was extractedwith ethyl acetate (100 mL×4). The combined extracts were washed withsaturated NaHCO₃ (100 mL×4). The aqueous solution was acidified withconcentrated HCl to pH=1, which, in turn, was extracted with ethylacetate (100 mL×4). The combined organic solution was dried over Na₂SO₄,filtered through Celite, and evaporated in vacuo to dryness.Recrystallization from toluene afforded 10.2 g (86%) of the desiredcompound as colorless crystals: mp 107-109° C. (lit. [214] mp 109-113°C. for the S-isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 3.63 (d, J=10.1 Hz,1H, CHH_(a)), 3.52 (d, J=10.1 Hz, 1H, CHH_(b)), 1.35 (s, 3H, Me); IR(KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C═O), 1449, 1421, 1380, 1292,1193, 1085 cm⁻¹; [α]_(D) ²⁶+10.5° (c=2.6, MeOH); Anal. Calcd. forC₄H₇BrO₃: C 26.25, H 3.86. Found: C 26.28, H 3.75.

Synthesis of(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide.Thionyl chloride (46.02 g, 0.39 mol) was added dropwise to a cooledsolution (less than 4° C.) of R-18 (51.13 g, 0.28 mol) in 300 mL of THFunder an argon atmosphere. The resulting mixture was stirred for 3 hunder the same condition. To this was added Et₃N (39.14 g, 0.39 mol) andstirred for 20 min under the same condition. After 20 min,5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF wereadded and then the mixture was allowed to stir overnight at roomtemperature. The solvent was removed under reduced pressure to give asolid which was treated with 300 mL of H₂O, extracted with EtOAc (2×400mL). The combined organic extracts were washed with saturated NaHCO₃solution (2×300 mL) and brine (300 mL). The organic layer was dried overMgSO₄ and concentrated under reduced pressure to give a solid, which waspurified from column chromatography using CH₂Cl₂/EtOAc (80:20) to give asolid. This solid was recrystallized from CH₂Cl₂/hexane to give 55.8 g(73.9%) of(2R)-3-Bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide(R-32a) as a light-yellow solid.

¹H NMR (CDCl₃/TMS) δ 1.66 (s, 3H, CH₃), 3.11 (s, 1H, OH), 3.63 (d,J=10.8 Hz, 1H, CH₂), 4.05 (d, J=10.8 Hz, 1H, CH₂), 7.85 (d, J=8.4 Hz,1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 1H, ArH), 8.12 (d, J=2.1 Hz, 1H,ArH), 9.04 (bs, 1H, NH). Calculated Mass: 349.99, [M-H]⁻ 349.0. M.p.:124-126° C.,

Synthesis of(S)-3-(4-chloro-3-fluorophenoxy)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide.A mixture of bromoamide((2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide,(R-19) 2.0 g, 5.70 mmol), anhydrous K₂CO₃ (2.4 g, 17.1 mmol) was heatedto reflux for 2 h and then concentrated under reduced pressure to give asolid. The resulting solid was treated with 4-chloro-3-fluorophenol (1.3g, 8.5 mmol) and anhydrous K₂CO₃ (1.6 g, 11.4 mmol) in 50 mL of2-propanol was heated to reflux for 3 h and then concentrated underreduced pressure to give a solid. The residue was treated with 100 mL ofH₂O and then extracted with EtOAc (2×100 mL). The combined EtOAcextracts were washed with 10% NaOH (4×100 mL) and brine, successively.The organic layer was dried over MgSO₄ and then concentrated underreduced pressure to give an oil which was purified by columnchromatography using EtOAc/hexane (50:50) to give a solid which wasrecrystallized from CH₂Cl₂/hexane to give 1.7 g (70.5%) of(S)-3-(4-chloro-3-fluorophenoxy)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamideas a colorless solid.

¹H NMR (CDCl₃/TMS) δ 1.60 (s, 3H, CH₃), 3.28 (s, 1H, OH), 3.98 (d,J=9.05 Hz, 1H, CH), 6.64-6.76 (m, 2H, ArH), 7.30 (d, J=8.67 Hz, 1H,Arm), 7.81 (d, J=8.52 Hz, 1H, ArH), 7.96 (q, J=2.07, 8.52 Hz, 1H, ArH),8.10 (d, J=2.07 Hz, 1H, ArH), 9.10 (s, 1H, NH). Calculated Mass:[M-H]-414.9. Mp: 132-134° C.

Example 2 Metabolic Stability of the Compounds of this Invention

Metabolic stability assays were performed in order to assess the invitro half-life of compounds of formula II when incubated with humanliver microsomes. The data generated was transformed to determineintrinsic clearance values. In a separate experiment, permeabilityacross human, intestinal epithelial monolayers (Caco-2 cells) was usedas a measure of intestinal permeability as well as an indicator ofefflux potential. Caco-2 cells are often used as an early screeningsurrogate for oral bioavailability. Microsomal half-life can beconverted to in vitro clearance values as a means to predict hepaticintrinsic clearance. Intrinsic clearance is defined as the functionalability of the liver to metabolize a drug or other compound.

Materials and Methods:

Metabolic Stability Measured in Human Liver Microsomes:

Compounds of formula II in this study were incubated at a finalconcentration of 0.6 μM. Microsome reactions were performed under eitherPhase I or “Phase I and II” conditions, where indicated. Compound stocks(10 mM ACN) were initially diluted to a concentration of 60 μM (in 60%ACN/H₂O) resulting in a “working stock” solution of 100×. Human livermicrosomes were utilized at a final concentration of 0.6 mg/ml.Duplicate wells were used for each time point (0, 6, 10, 30, and 60minutes). Reactions were carried out at 37° C. in a shaking water bath,and the final concentration of solvent was kept constant at 0.6%. Thefinal volume for each reaction was 600 μl, comprised of 368 μl of 100 mMKPO₄ buffer, (pH 7.4); 12.6 μl of HLM (from a 20 mg/ml stock); 6 μl of100×“working stock” drug compound, and 126 μl of NRS “master mix”solution. At each time point, 100 μl of reaction was removed and addedto a sample well containing 100 μl of ice-cold, 100% ACN (plus internalstandards), to stop the reaction. The NRS “master mix” is a solution ofglucose 6-phosphate dehydrogenase, NADP⁺, MgCl₂, and glucose6-phosphate, prepared per manufacturer's instructions (BD Biosciences,Waltham, Mass.). Each 6.0 ml stock of NRS “master mix” solution contains3.8 ml H₂O, 1.0 ml solution “A” (Cat. #461220), and 0.2 ml solution “B”(Cat. #461200). Human liver microsomes (lot #0610279, Xenotech Corp.)represented a pool of 60 donors.

Samples were centrifuged at 3,000 rpm for 10 minutes at 4° C. to removedebris and precipitated protein. Approximately 160 μl of supernatant wassubsequently transferred to a new sample block for analysis. Theconcentration of parent drug remaining in each well (expressed aspercent remaining versus Time ‘0’, at the beginning of the reaction) wasmeasured by LC/MS, as detailed below. The intrinsic clearance rates(CLint) were calculated from 0-60 minutes based on first order decaykinetics as a function of microsomal protein concentration.

Permeability across Human, Intestinal Epithelial Monolayers:

Permeability was measured in the Apical (pH 6.6) to Basolateral (pH 7.4)and Basolateral (pH 7.4) to Apical (pH 6.6) directions across polarized,Caco-2 epithelial monolayers. Compound stocks (10 mM acetonitrile) weretested in the study at a final concentration of 10 μM. The concentrationof drug in the receiver well was measured by LC/MS/MS using a standardcurve. The apparent permeability (Papp) for each compound wascalculated, and values (A-B) were classified as: Poor (Papp: <1), Low(Papp 1-2), Medium (Papp 2-10) or High (Papp>10).Papp(×10⁻⁶ cm/sec)=Amount transported/(Area*Initial concentration*Time)Papp(cm/s)=[V/(A*Ci)]*(Cf/T)V=volume of the receptor chamber (ml, or cm³)A=area of the membrane insert (cm²)Ci=initial concentration of drug (μM)Cf=final concentration of drug (μM)T=assay time (seconds)Analytical Methods:

All samples were analyzed on the MDS/Sciex API4000 Q Trap system withelectrospray ionization (ESI) in the positive or negative SIM mode,depending on the compounds. The mobile phases were isocratic at 30% A(0.1% formic acid in water) and 70% B (0.1% formic acid in acetonitrile)with a flow rate of 0.4 m/min. A Phenomenex Luna Phenyl-Hexyl column(60×2.0 mm ID, 6μ) was used. The injection volume was 10 μL. The totalrun time per sample was 1.6 to 3.0 minutes. Tamoxifen and diclofenacwere used as internal standards for the positive and negative mode,respectively. The percentage of parent drug compound remaining aftereach time point was determined relative to the initial measuredconcentration at the beginning of the reaction (T₀ min).

Data Analysis:

For half-life determination, data was fitted using GraphPad Prism, v4.03 with the non-linear regression equation “one phase exponentialdecay” defined as:Y=Span*exp(−K*X)+Plateau (decays to Plateau with a first-order rateconstant, K).“−K” is the slope of the curve. The half life (minutes), T_(1/2), =ln0.6/−K and is therefore defined as −0.693/−K, or 0.693/K, a/k/a−0.693/slope). Intrinsic Clearance (μl/min/mg protein) is defined as:CLint=0.693*(1/T_(1/2))*(ml incubation/mg protein)*1000; This equationcan also be expressed as (K*1000)/microsome conc.

Results: TABLE 1 Metabolic Stability Measured in Human Liver Microsomes:Half Life CL_(int) Compound (minutes) (ul/min/mg) Half Life CL_(int)having Phase I Phase I (minutes) (ul/min/mg) formula only only Phase I +II Phase I + II II Stable <1 Stable <1

The results had shown that in vitro half-life as determined from themicrosomal assays demonstrated that compound of formula (II) under bothphase I and phase I/II metabolic conditions. As shown in Table 1, thecompound didn't exhibit an intrinsic clearance (CLint) value greaterthan 10 μl/min/mg. It is generally accepted that an in vitro CLint valueof less than 10 μl/min/mg protein represents favorable metabolicstability of the test compound. Compound of formula II exhibited lowclearance in human liver microsomes. In conclusion, based on the datareported herein, compound of formula (II) exhibited favorable metabolicstability profiles in vivo studies.

Example 3 Androgen Receptor Binding Affinity of SARMs

Materials and Methods:

The androgen receptor (AR) binding affinity of SARMs was determined byusing an in vitro competitive radioligand binding assay with[17α-methyl-³H]-Mibolerone ([³H]MIB, PerkinElmer), a high affinity ARligand. Recombinant androgen receptor ligand binding domain (AR LBD) wascombined with [³H]MIB in buffer A (10 mM Tris, pH 7.4, 1.6 mM disodiumEDTA, 0.26 M sucrose, 10 mM sodium molybdate, 1 mM PMSF) to determinethe equilibrium dissociation constant (K_(d)) of [³H]MIB. Protein wasincubated with increasing concentrations of [³H]MIB with and without ahigh concentration of unlabeled MIB in order to determine total andnon-specific binding. Non-specific binding was then subtracted fromtotal binding to determine specific binding and graphed using SigmaPlotand non-linear regression for ligand binding curve with one sitesaturation to determine the K_(d) of MIB (1.84 nM). In addition, theconcentration of [³H]MIB required to saturate AR LBD was determined tobe 4 nM.

Compound of formula (II) was tested in a range of concentrations from10⁻¹¹ to 10⁻⁶ M using the conditions described above. Followingincubation, plates were harvested with GF/B filters on the Unifilter-96Harvester (PerkinElmer) and washed three times with ice-cold buffer B(60 mM Tris, pH 7.2). The filter plates were dried at RT, then 36 μlMicroscint-O cocktail was added to each well and sealed with TopSeal-A.The receptor bound radioligand was then determined with the TopCount®NXT Microplate Scintillation Counter (PerkinElmer).

The specific binding of [³H]MIB at each concentration of SARM wasdetermined by subtracting the nonspecific binding of [³H]MIB (determinedby incubating with 10⁻⁶ M unlabeled MIB), and expressed as a percentageof the specific binding in the absence of each SARM. The concentrationof SARM required to decrease the [³H]MIB binding by 60%, IC₆₀ value, wasdetermined by computer-fitting the data with SigmaPlot and non-linearregression with the standard curve four parameter logistic curve. Theequilibrium binding constant (K_(i)) of each compound was thendetermined with the following equation:K _(i) =K _(d) ×IC ₆₀/(K _(d) +L)where K_(d) is the equilibrium dissociation constant of [³H]MIB (1.84nM), and L is the concentration of [³H]MIB (4 nM).Results:The binding affinity for compound of formula (II) was tested in theradioligand binding assay with AR LBD as the receptor with K_(i)(nM)=8.1

Example 4 Preclinical Anabolic and Androgenic Pharmacology of Compounds(II) in Intact and Castrate Male Rats

Anabolic and androgenic efficacy of Compound of formula (II)administered by daily oral gavage were tested. The S-isomer of compound(II) was synthesized and tested as described herein

Materials and Methods:

Male Sprague-Dawley rats weighing approximately 200 g were purchasedfrom Harlan Bioproducts for Science (Indianapolis, Ind.). The animalswere maintained on a 12-h light/dark cycle with food (7012C LM-485Mouse/Rat Sterilizable Diet, Harlan Teklad, Madison, Wis.) and wateravailable ad libitum. The animal protocol was reviewed and approved bythe Institutional Animal Care and Use Committee of the University ofTennessee. The anabolic and androgenic activity of compounds of formula(II) in intact animals, acutely orchidectomized (ORX) animals andchronically (9 days) ORX rats.

The test article for this study was weighed and dissolved in 10% DMSO(Fisher) diluted with PEG 300 (Acros Organics, NJ) for preparation ofthe appropriate dosage concentrations. The animals were housed in groupsof 2 to 3 animals per cage. Animals were randomly assigned to one ofseven groups consisting of 4 to 5 animals per group. Control groups(intact and ORX) were administered vehicle daily. Compound of formula(II) was administered via oral gavage at doses of 0.01, 0.03, 0.1, 0.3,0.75, and 1 mg/day to both intact and ORX groups. Where appropriate,animals were castrated on day one of the study. Treatment with compoundof formula (II) began nine days post ORX and was administered daily viaoral gavage for fourteen days.

The animals were sacrificed under anesthesia (ketamine/xyalzine, 87:13mg/kg) and body weights were recorded. In addition, ventral prostate,seminal vesicles, and levator ani muscle were removed, individuallyweighed, normalized to body weight, and expressed as a percentage ofintact control. Student's T-test was used to compare individual dosegroups to the intact control group. Significance was defined a priori asa P-value <0.05. Ventral prostate and seminal vesicle weights wereevaluated as a measure of androgenic activity, whereas levator animuscle weight was evaluated as a measure of anabolic activity. Blood wascollected from the abdominal aorta, centrifuged, and sera were frozen at−80° C. prior to determination of serum hormone levels. Serumluteinizing hormone (LH) and follicle stimulating hormone (FSH)concentrations were determined.

Results:

A series of dose-response studies in intact and castrated rats in orderto evaluate the potency and efficacy of compound of formula (II) in bothandrogenic (prostate and seminal vesicles) and anabolic (levator animuscle) tissue was conducted. In intact animals, compound of formula(II) treatment resulted in decreases in the weight of both prostate andseminal vesicles while the levator ani muscle weight was significantlyincreased. Levator ani muscle weight following Compound II treatmentwere 100%±10%, 98%±7%, 110%±5%, 110%±5%, 125%±10%, and 129%±10% ofintact controls following doses of 0.01, 0.03, 0.1, 0.3, 0.75, and 1mg/day, respectively. The prostate weights were 117%±20%, 98%±15%,82%±20%, 62%±5%, 107%±30%, and 110%±14% of intact controls followingdoses of 0.01, 0.03, 0.1, 0.3, 0.75, and 1 mg/day, respectively. Theseresults are significant since current androgen therapies arecontraindicated in some patient populations due to the proliferativeandrogenic effects in prostate and breast tissues. However, manypatients in these populations could benefit from the anabolic actions ofandrogens in muscle and bone. Since compound of formula (I) exhibitedtissue selective anabolic effects, it may be possible to treat patientgroups in which androgens were contraindicated in the past.

In castrated, ORX animals, prostate weights following Compound IItreatment were 10%±3%, 12%±3%, 26%±7%, 39%±6%, 60%±14%, 88%±16%, and123%±22% of intact controls following doses of 0, 0.01, 0.03, 0.1, 0.3,0.75, and 1 mg/day, respectively (FIG. 2). Similarly, seminal vesicleweights were 11%±1%, 11%±1%, 11%±1%, 27%±14%, 58%±18%, 86%±12%, and100%±8% of intact controls following doses of 0, 0.01, 0.03, 0.1, 0.3,0.75, and 1 mg/day, respectively (FIG. 2). Significant increases wereseen in levator ani muscle weights of in all dose groups, when comparedto intact controls. The levator ani muscle weights were 48%±8%, 50%±5%,62%±6%, 89%±10%, 118%±6%, 134%±8% and 129%±14% of intact controlscorresponding to 0, 0.01, 0.03, 0.1, 0.3, 0.75, and 1.0 mg/day dosegroups, respectively (FIG. 2).

Testosterone propionate (TP) andS-3-(4-Acetylaminophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (S-4), maximally stimulated the levator ani muscle weightto 104% and 101%, respectively. These data show that compound of formula(I) exhibited significantly greater efficacy and potency than either TPor S-4. As a whole, these data show that compound I is able to stimulatemuscle growth in the presence or absence of testosterone while exertinganti-proliferative effects on the prostate. These data show that thatcompound of formula (II) restore lost muscle mass in patients withsarcopenia or cachexia. Additionally, the antiproliferative effects ofcompound of formula (II) on the prostate may allow some patientpopulations, in which androgens are currently contraindicated, access toanabolic agents.

Compound II exhibited anabolic muscle/prostate ratio in castrated ratsof 4.10, 2.39, 2.28, 1.97, 1.53, 1.05 following doses of 0.01, 0.03,0.1, 0.3, 0.75 and 1 mg/day, respectively.

Pharmacology results following 1 mg/day of compound II exhibited thatprostate weight was 110%±14% of intact control and levator ani muscleweight was 129%±10% of intact control. Compound I maintained prostateweight following orchidectomy at 123±22% of intact controls and levatorani muscle weight at 129±14% of intact controls. A range of between 0.1mg/day to 0.3 mg/day of Compound II restored 100% of levator ani muscleweight, while between 39 to 60% prostate weight was restored.

Example 5 In Vitro CYP Inhibition Assay

Materials and Methods:

P450 enzyme inhibition was measured using human cDNA-expressed CYP3A4,2D6, 2C19, 2C9, and 1A2 recombinant enzymes and fluorogenic substrates(coumarin analogues) that are converted to fluorescent products. Theanalogues utilized for each isoenzyme are as follows:7-Benzyloxy-trifluoromethylcoumarin, (BFC) for 3A4;3-[2-(N,N-diethyl-N-methyl amino)ethyl] 7-methoxy-4-methylcoumarin,(AMMC) for 2D6; 3-Cyano-7-Ethoxycoumarin, (CEC) for 2C19 and 1A2; and7-Methoxy-4-trifluoro-methylcoumarin, (MFC) for 2C9. These substrateswere utilized at a single concentration (either 50 μM or 75 μM) at ornear the apparent Km for each substrate. Fluorescence intensity wasmeasured using a Wallac 1420 Victor³ Multi-label Counter Model(Perkin-Elmer, Wellesley, Mass.), with an excitation wavelength filterof 405 nm, and an emission filter of 460 nm (535 nm for the 3A4 and 2C9substrates). Compound stocks (10 mM in a 4:1 ratio of acetonitrile:DMSO) were tested in this study using an 8-point dose response curve induplicate (ranging from 0.15 μM-20.0 μM). The concentration ofacetonitrile was kept constant at 0.4%, and the reaction was carried outat 37° C. for 30 minutes. Averages (minus background) and IC₅₀ valueswere calculated.

Results:

The in-vitro screening results for potential drug-drug interactions(DD1) of SARM compound of formula II is presented in Table 2: TABLE 2CYP (P450) Inhibition, IC50 (μM) Compound 3A4 2D6 2C19 2C9 1A2 II >2017.7 2.4 1.3 >20

Example 6 Pharmacokinetics of Compound (II) in Dogs

In order to determine the pharmacokinetics of Compound II, the compoundwas administered to beagle dogs perorally, and circulating plasmalevels, terminal elimination half-life (t1/2), total body clearance(CL), terminal volume distribution (Vz) and absolute bioavailability (F%) (Table 3) were determined. Compound I was rapidly and completely.TABLE 3 Compound II T½ (hr)  37 ± 26.8 CL (mL/min/kg) 0.36 ± 0.12 Vz(mL/kg) 1266 ± 352  F % 72.5%

Example 7 Anabolic and Androgenic Activity of SARM Compounds in Intactand Castrated Male Rats

The in vivo pharmacological activity of each synthetic AR ligand (listedin Table 4, below) was examined in five male Sprague-Dawley ratsweighing approximately 200 g. Animals were castrated via a scrotalincision under anesthesia 24 h before drug treatments and received dailysc injections of the compound of interest at a dose rate of 1 mg/d for14 d. All compounds of interest were freshly dissolved in vehiclecontaining dimethylsulfoxide (5%, vol/vol) in polyethylene glycol 300before dose administration. An additional two groups of animals with orwithout castration received vehicle only and served as castrated orintact control groups, respectively. Animals were killed at the end ofthe treatment. Plasma samples were collected and stored at −80 C forfuture use. The ventral prostate, seminal vesicles, and levator animuscle were removed, cleared of extraneous tissue, and weighed. Allorgan weights were normalized to body weight and compared. The weightsof prostate and seminal vesicles were used to evaluate androgenicactivity, whereas the levator ani muscle weight was used as a measure ofanabolic activity. The results are summarized in FIGS. 2 and 3. TABLE 4

Compound R1 R2 R3 R4 R5 S-1 H H F H H C-1 F H F H H C-2 CH3 H F H H C-3H F F H H C-4 H Cl F H H C-6 H F Cl H H C-8 F H Cl H H C-10 H Cl Cl H HC-11 H F NO₂ H H C-12 F H NO₂ H H C-13 F F F H H C-14 F F H F H C-17 F HF H F C-18 F H F F H C-22 Cl H Cl Cl H C-23 F F F F F

It will be appreciated by a person skilled in the art that the presentinvention is not limited by what has been particularly shown anddescribed hereinabove. Rather, the scope of the invention is defined bythe claims that follow:

1. A compound represented by the structure of formula (I):

wherein Q₂ is alkyl, F, Cl, Br, I, CF₃, CN, C(R)₃, Sn(R)₃, N(R)₂,NHCOCH₃, NHCOCF₃, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃,NHCSCF₃, NHCSR NHSO₂CH₃, NHSO₂R, OR, COR, OCOR, OSO₂R, SO₂R, SR; and Ris alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH₂F, CHF₂, CF₃, CF₂CF₃,aryl, phenyl, F, Cl, Br, I, alkenyl or OH; or its isomer,pharmaceutically acceptable salt, pharmaceutical product, N-oxide,hydrate or any combination thereof.
 2. The compound of claim 1, whereinsaid compound is represented by the structure of formula II:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate or any combination thereof.
 3. A composition comprisingcompound of claim 1, and a pharmaceutically acceptable carrier, diluentor salt or a combination thereof.
 4. The composition of claim 3, whereinsaid composition further comprises a therapeutic agent, which is ananti-cancer agent, an immunomodulating agent, an agent treatingdiabetes, an agent treating the nervous system, an agent treating thecardiovascular system, an agent treating the gastrointestinal system, anagent treating a dermatological disease, or condition, an anti-infectiveagent, an agent treating the liver, an agent treating the kidney, anagent treating a metabolic disease, an agent treating a wasting disease,a gene therapy agent, an agent treating the endocrine system, a vitamin,a stomatognathic agent, a urogenital agent, behavior-modulating agent,an agent treating the respiratory system, an agent treating the hemicsystem, an agent treating an ophthalmic disease, or any combinationthereof.
 5. The composition of claim 4, wherein said therapeutic agentis an anti-androgen, an antiestrogen, a monoclonal antibody, achemotherapeutic agent, an immunosuppressive or anti-inflammatory agent,an immunostimulatory agent, a sulfonylurea, meglitnide, insulin,biguanide, thiazolidinedione, or alpha-glucosidase inhibitor, anadrenomimetic agent, adrenoceptor antagonist, cholinomimetic agent, amuscarinic blocker, a ganglionic blocker, an anesthetic agent, ananalgesic agent, an agent treating neuromuscular transmission, a nervoussystem stimulant, a sedative agent, neurodegenerative disordermedication, antiepileptic agent, antipsychotic agent, anti-addictionagent, an anti-arrhythmic agent, an anti-anginal agent, a vasocativeagent, a calcium channel blocker, an antihypertensive agent, a diureticagent, an anticoagulant or fibrinolytic agent, a hypocholesterolemicagent, an opioid, 5-HT₃ receptor antagonist, adsorbent agent, bulkingagent, a stool softening or laxative agent, cathartic agent, anantiemetic agent, an emetic agent, an antacid agent, an H₂-receptorantagonist, a proton pump inhibitor, a 5-aminosalicylate agent, aprostaglandin, a glucocorticosteroid, a retinoid, photochemotherapeuticagent, a photodynamic agent, aminolevulinic acid, dapsone, pyrethrin,pyrethroid, thalidomide, an antimalarial agent, an antimicrobial agent,an antifungal agent, an antiviral agent, a sulfonamide, a trimethoprimagent, a quinolone agent, an oxazolidinone agent, an antiseptic agent, abeta-lactam agent, an aminoglycoside agent, a tetracycline agent, achloramphenicol agent, a macrolide agent, a lincosamide agent, abacitracin agent, a glycopeptide agent, a polymyxin agent, anantiprotozoal agent, an antithelmintic agent, a cortisone, a colchicine,a methotrexate, a ursodeoxycholic acid, a penicillamine, a vitamin,glucosidase alpha, sodium bicarbonate, bisphosphonate, biotin,allopurinol, levodopa, diazepam, phenobarbital, haloperidol, folic acid,haptoglobin, carnitine, a steroid, cannabinoid metoclopramid, cisapride,medroxyprogesterone acetate, megestrol acetate, cyproheptadine,hydrazine sulfate, pentoxifylline, thalidomide, anticytokine antibodies,cytokine inhibitors, eicosapentaenoic acid, indomethacin, ibuprofen,melatonin, insulin, growth hormone, clenbuterol, pancreas extract,cabergoline, bromocriptine, thyroxine, gonadotropin, glucocorticoid,glucocorticoid analogue, corticotrophin, metyrapone, aminoglutethimide,mitotane, ketoconazole, mifepristone, dexamethasone somatostatinanalogue, gonadotropin-releasing hormone analogue, leuprolide,goserelin, antidiuretic hormone, antidiuretic hormone analogue,oxytocin, estrogen, progestin, specific estrogen receptor modulator(SERM), uterine, stimulant, uterine relaxant, androgen, antiandrogen,prostaglandin, dopamine receptor agonist, alpha-adrenoreceptor blocker,anabolic steroid, an antianxiety agent, an antipsychotic agent, anantidepressant, beta-2 agonist, anticholinergic bronchodilator,theophylline, aminophylline, nedocromil sodium, sodium cromoglycate,leukotriene receptor antagonist, corticosteroid, expectorant, mucolyticagent, antihistamine, pseudoephedrine, or a neuraminidase inhibitor,betagan, betimol, timoptic, betoptic, betoptic, ocupress, optipranolol,xalatan, alphagan, azopt, trusopt, cospot, pilocar, pilagan, propine,opticrom, acular, livostin, alomide, emadine, patanol, alrex, dexacidin,maxitrol, tobradex, blephamide, ocufen, voltaren, profenal, pred forte,econpred plus, eflone, flarex, inflamase forte, inflamase mild, lotemax,vexol, polytrim, illotycin, ciloxan, ocuflox, tobrex, or garamycin, orany combination thereof.
 6. A method of binding a compound to anandrogen receptor, comprising the step of contacting the androgenreceptor with the selective androgen receptor modulator compound ofclaim 1 or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, hydrate, N-oxide or any combination thereof, in anamount effective to bind the compound to the androgen receptor.
 7. Amethod of contraception in a male subject, comprising the step ofadministering to said subject the compound of claim 1 or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,hydrate, N-oxide or any combination thereof, in an amount effective tosuppress sperm production in said subject, thereby effectingcontraception in said subject.
 8. A method of hormone therapy comprisingthe step of contacting an androgen receptor of a subject with compoundof claim 1 or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, hydrate, N-oxide or any combinationthereof, in an amount effective to effect a change in anandrogen-dependent condition.
 9. A method of treating a subjectsuffering from prostate cancer, comprising the step of administering tosaid subject compound of claim 1 or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, hydrate, N-oxide orany combination thereof, in an amount effective to treat prostate cancerin said subject.
 10. A method of delaying the progression of prostatecancer in a subject suffering from prostate cancer, comprising the stepof administering to said subject the compound of claim 1, or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,hydrate, N-oxide or any combination thereof in an amount effective todelay the progression of prostate cancer in said subject.
 11. A methodof treating a bone-related disorder in a subject, or increasing a bonemass in a subject, promoting bone formation in a subject, comprising thestep of administering to said subject the compound of claim 1 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, hydrate, N-oxide or any combination thereof, in an amounteffective to treat said bone-related disorder.
 12. The method of claim11, wherein said subject suffers from osteoporosis, osteopenia,increased bone resorption, bone fracture, bone frailty, loss of bonemineral density (BMD), or any combination thereof.
 13. The method ofclaim 11, wherein said method increases the strength of a bone of saidsubject.
 14. The method of claim 11, wherein said compound stimulates orenhances osteoblastogenesis.
 15. The method of claim 11, wherein saidcompound inhibits osteoclast proliferation.
 16. A method of treating,reducing the incidence of, delaying progression of, reducing theseverity of, or alleviating symptoms associated with a muscle wastingdisorder in a subject, comprising the step of administering to saidsubject the compound of claim 1 or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, hydrate, N-oxide orany combination thereof, in an amount effective to treat said musclewasting disorder in said subject.
 17. The method of claim 16, whereinsaid muscle wasting disorder is due to a pathology, illness, disease orcondition.
 18. The method of claim 17, wherein said pathology, illness,disease or condition is neurological, infectious, chronic or genetic.19. The method of claim 17, wherein said pathology, illness, disease orcondition is a Muscular Dystrophy, a Muscular Atrophy, X-linkedspinal-bulbar Muscular Atrophy (SBMA), a Cachexia, malnutrition,Leprosy, Diabetes, Renal Disease, Chronic Obstructive Pulmonary Disease(COPD), Cancer, end stage Renal failure, Sarcopenia, Emphysema,Osteomalacia, HIV Infection, AIDS, or Cardiomyopathy.
 20. The method ofclaim 16, wherein said muscle wasting disorder is an age-associatedmuscle wasting disorder; a disuse deconditioning-associated musclewasting disorder; or the muscle wasting disorder is due to chronic lowerback pain; burns; central nervous system (CNS) injury or damage;peripheral nerve injury or damage; spinal cord injury or damage;chemical injury or damage; or alcoholism.
 21. A method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of diabetes in a human subject, comprisingthe step of administering an effective amount of the compound of claim1, or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, hydrate, N-oxide or any combination thereof to saidsubject.
 22. A method of treating, reducing the severity of, reducingthe incidence of, delaying the onset of, or reducing pathogenesis ofglucose intolerance in a human subject, comprising the step ofadministering an effective amount of the compound of claim 1 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, hydrate, N-oxide or any combination thereof to said subject.23. A method of treating, reducing the severity of, reducing theincidence of, delaying the onset of, or reducing pathogenesis ofhyperinsulinemia in a human subject, comprising the step ofadministering an effective amount of the compound of claim 1 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, hydrate, N-oxide or any combination thereof to said subject.24. A method of treating, reducing the severity of, reducing theincidence of, delaying the onset of, or reducing pathogenesis of insulinresistance in a human subject, comprising the step of administering aneffective amount of the compound of claim 1 or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,hydrate, N-oxide or any combination thereof to said subject.
 25. Amethod of treating, reducing the severity of, reducing the incidence of,delaying the onset of, or reducing pathogenesis of diseases associatedwith diabetes comprising the step of administering an effective amountof the compound of claim 1 or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, hydrate, N-oxide or anycombination thereof to said subject.
 26. A method of treating, reducingthe severity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of fatty liver conditions in a human subject,comprising the step of administering an effective amount of the compoundof claim 1 or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, hydrate, N-oxide or any combinationthereof to said subject.
 27. A method of treating, reducing the severityof, reducing the incidence of, delaying the onset of, or reducingpathogenesis of cardiovascular disease in a human subject, comprisingthe step of administering an effective amount of the compound of claim 1or its isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, hydrate, N-oxide or any combination thereof to said subject.28. A method of treating reducing the severity of, reducing theincidence of, delaying the onset of, or reducing pathogenesis ofcachexia in a subject, comprising the step of administering an effectiveamount of the compound of claim 1 or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, hydrate, N-oxide orany combination thereof to said subject.
 29. A method of treating adisease or condition of the eye of a subject, comprising the step ofadministering an effective amount of a compound of claim 1 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof to said subject.30. The method of claim 29, wherein the disease or condition of the eyecomprises Sjogren's syndrome, or xerophthalmia.
 31. A method of reducinga fat mass in a subject comprising the step of administering aneffective amount of a compound of claim 1 or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof to said subject.
 32. Amethod of increasing a lean mass in a subject comprising the step ofadministering an effective amount of a compound of claim 1 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof to said subject.33. A compound represented by the structure of formula III:

wherein X is a bond, O, CH₂, NH, Se, PR, NO or NR; G is O or S; T is OH,OR, —NHCOCH₃, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl,trihaloalkyl, CH₂F, CHF₂, CF₃, CF₂CF₃, aryl, phenyl, halogen, alkenyl orOH; R₁ is CH₃, CH₂F, CHF₂, CF₃, CH₂CH₃, or CF₂CF₃; R₂ is H, F, Cl, Br,I, CH₃, CF₃, OH, CN, NO₂, NHCOCH₃, NHCOCF₃, NHCOR, alkyl, arylalkyl, OR,NH₂, NHR, N(R)₂, SR; R₃ is H, F, Cl, Br, I, CN, NO₂, COR, COOH, CONHR,CF₃, Sn(R)₃, or R₃ together with the benzene ring to which it isattached forms a fused ring system represented by the structure:

Z is NO₂, CN, Cl, F, Br, I, COR, COOH, or CONHR; Y is CF₃, alkoxy,alkyl, hydroxyalkyl, alkylaldehyde, formyl, F, Br, Cl, I, CN, or Sn(R)₃;Q is alkyl, halogen, CF₃, CN CR₃, Sn(R)₃, N(R)₂, NHCOCH₃, NHCOCF₃,NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH₃, NHCSCF₃, NHCSR NHSO₂CH₃,NHSO₂R, OH, OR, COR, OCOR, OSO₂R, SO₂R, SR; or Q together with thebenzene ring to which it is attached is a fused ring system representedby structure A, B or C:

n is an integer of 1-4; and m is an integer of 1-3; wherein if R₃ is H,R₂ is not H. or its isomer, pharmaceutically acceptable salt,pharmaceutical product, N-oxide, hydrate or any combination thereof. 34.The compound of claim 33, wherein said compound is characterized by thestructure of formula IV:


35. The compound of claim 33, wherein said compound is characterized bythe structure of formula II:


36. A composition comprising compound of claim 33, and apharmaceutically acceptable carrier, diluent or salt or a combinationthereof.
 37. The composition of claim 36, wherein said compositionfurther comprises a therapeutic agent, which is an anti-cancer agent, animmunomodulating agent, an agent treating diabetes, an agent treatingthe nervous system, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating adermatological disease, or condition, an anti-infective agent, an agenttreating the liver, an agent treating the kidney, an agent treating ametabolic disease, an agent treating a wasting disease, a gene therapyagent, an agent treating the endocrine system, a vitamin, astomatognathic agent, a urogenital agent, behavior-modulating agent, anagent treating the respiratory system, an agent treating the hemicsystem, an agent treating an ophthalmic disease, or any combinationthereof.
 38. The composition of claim 37, wherein said therapeutic agentis an anti-androgen, an antiestrogen, a monoclonal antibody, achemotherapeutic agent, an immunosuppressive or anti-inflammatory agent,an immunostimulatory agent, a sulfonylurea, meglitnide, insulin,biguanide, thiazolidinedione, or alpha-glucosidase inhibitor, anadrenomimetic agent, adrenoceptor antagonist, cholinomimetic agent, amuscarinic blocker, a ganglionic blocker, an anesthetic agent, ananalgesic agent, an agent treating neuromuscular transmission, a nervoussystem stimulant, a sedative agent, neurodegenerative disordermedication, antiepileptic agent, antipsychotic agent, anti-addictionagent, an anti-arrhythmic agent, an anti-anginal agent, a vasocativeagent, a calcium channel blocker, an antihypertensive agent, a diureticagent, an anticoagulant or fibrinolytic agent, a hypocholesterolemicagent, an opioid, 5-HT₃ receptor antagonist, adsorbent agent, bulkingagent, a stool softening or laxative agent, cathartic agent, anantiemetic agent, an emetic agent, an antacid agent, an H₂-receptorantagonist, a proton pump inhibitor, a 5-aminosalicylate agent, aprostaglandin, a glucocorticosteroid, a retinoid, photochemotherapeuticagent, a photodynamic agent, aminolevulinic acid, dapsone, pyrethrin,pyrethroid, thalidomide, an antimalarial agent, an antimicrobial agent,an antifungal agent, an antiviral agent, a sulfonamide, a trimethoprimagent, a quinolone agent, an oxazolidinone agent, an antiseptic agent, abeta-lactam agent, an aminoglycoside agent, a tetracycline agent, achloramphenicol agent, a macrolide agent, a lincosamide agent, abacitracin agent, a glycopeptide agent, a polymyxin agent, anantiprotozoal agent, an antithelmintic agent, a cortisone, a colchicine,a methotrexate, a ursodeoxycholic acid, a penicillamine, a vitamin,glucosidase alpha, sodium bicarbonate, bisphosphonate, biotin,allopurinol, levodopa, diazepam, phenobarbital, haloperidol, folic acid,haptoglobin, carnitine, a steroid, cannabinoid metoclopramid, cisapride,medroxyprogesterone acetate, megestrol acetate, cyproheptadine,hydrazine sulfate, pentoxifylline, thalidomide, anticytokine antibodies,cytokine inhibitors, eicosapentaenoic acid, indomethacin, ibuprofen,melatonin, insulin, growth hormone, clenbuterol, pancreas extract,cabergoline, bromocriptine, thyroxine, gonadotropin, glucocorticoid,glucocorticoid analogue, corticotrophin, metyrapone, aminoglutethimide,mitotane, ketoconazole, mifepristone, dexamethasone somatostatinanalogue, gonadotropin-releasing hormone analogue, leuprolide,goserelin, antidiuretic hormone, antidiuretic hormone analogue,oxytocin, estrogen, progestin, specific estrogen receptor modulator(SERM), uterine, stimulant, uterine relaxant, androgen, antiandrogen,prostaglandin, dopamine receptor agonist, alpha-adrenoreceptor blocker,anabolic steroid, an antianxiety agent, an antipsychotic agent, anantidepressant, beta-2 agonist, anticholinergic bronchodilator,theophylline, aminophylline, nedocromil sodium, sodium cromoglycate,leukotriene receptor antagonist, corticosteroid, expectorant, mucolyticagent, antihistamine, pseudoephedrine, or a neuraminidase inhibitor,betagan, betimol, timoptic, betoptic, betoptic, ocupress, optipranolol,xalatan, alphagan, azopt, trusopt, cospot, pilocar, pilagan, propine,opticrom, acular, livostin, alomide, emadine, patanol, alrex, dexacidin,maxitrol, tobradex, blephamide, ocufen, voltaren, profenal, pred forte,econpred plus, eflone, flarex, inflamase forte, inflamase mild, lotemax,vexol, polytrim, illotycin, ciloxan, ocuflox, tobrex, or garamycin, orany combination thereof.
 39. A method of binding a compound to anandrogen receptor, comprising the step of contacting the androgenreceptor with the selective androgen receptor modulator compound ofclaim 33 or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, hydrate, N-oxide or any combination thereof, in anamount effective to bind the compound to the androgen receptor.
 40. Amethod of contraception in a male subject, comprising the step ofadministering to said subject the compound of claim 33 or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,hydrate, N-oxide or any combination thereof, in an amount effective tosuppress sperm production in said subject, thereby effectingcontraception in said subject.
 41. A method of hormone therapycomprising the step of contacting an androgen receptor of a subject withcompound of claim 33 or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, hydrate, N-oxide or any combinationthereof, in an amount effective to effect a change in anandrogen-dependent condition.
 42. A method of treating a subjectsuffering from prostate cancer, comprising the step of administering tosaid subject compound of claim 33 or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, hydrate, N-oxide orany combination thereof, in an amount effective to treat prostate cancerin said subject.
 43. A method of delaying the progression of prostatecancer in a subject suffering from prostate cancer, comprising the stepof administering to said subject the compound of claim 33, or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, hydrate, N-oxide or any combination thereof in an amounteffective to delay the progression of prostate cancer in said subject.44. A method of treating a bone-related disorder in a subject, orincreasing a bone mass in a subject, promoting bone formation in asubject, comprising the step of administering to said subject thecompound of claim 33 or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, hydrate, N-oxide or any combinationthereof, in an amount effective to treat said bone-related disorder. 45.The method of claim 44, wherein said subject suffers from osteoporosis,osteopenia, increased bone resorption, bone fracture, bone frailty, lossof bone mineral density (BMD), or any combination thereof.
 46. Themethod of claim 44, wherein said method increases the strength of a boneof said subject.
 47. The method of claim 44, wherein said compoundstimulates or enhances osteoblastogenesis.
 48. The method of claim 44,wherein said compound inhibits osteoclast proliferation.
 49. A method oftreating, reducing the incidence of, delaying progression of, reducingthe severity of, or alleviating symptoms associated with a musclewasting disorder in a subject, comprising the step of administering tosaid subject the compound of claim 33 or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, hydrate, N-oxide orany combination thereof, in an amount effective to treat said musclewasting disorder in said subject.
 50. The method of claim 49, whereinsaid muscle wasting disorder is due to a pathology, illness, disease orcondition.
 51. The method of claim 50, wherein said pathology, illness,disease or condition is neurological, infectious, chronic or genetic.52. The method of claim 50, wherein said pathology, illness, disease orcondition is a Muscular Dystrophy, a Muscular Atrophy, X-linkedspinal-bulbar Muscular Atrophy (SBMA), a Cachexia, malnutrition,Leprosy, Diabetes, Renal Disease, Chronic Obstructive Pulmonary Disease(COPD), Cancer, end stage Renal failure, Sarcopenia, Emphysema,Osteomalacia, HIV Infection, AIDS, or Cardiomyopathy.
 53. The method ofclaim 49, wherein said muscle wasting disorder is an age-associatedmuscle wasting disorder; a disuse deconditioning-associated musclewasting disorder; or the muscle wasting disorder is due to chronic lowerback pain; burns; central nervous system (CNS) injury or damage;peripheral nerve injury or damage; spinal cord injury or damage;chemical injury or damage; or alcoholism.
 54. A method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of diabetes in a human subject, comprisingthe step of administering an effective amount of the compound of claim33, or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, hydrate, N-oxide or any combination thereof to saidsubject.
 55. A method of treating, reducing the severity of, reducingthe incidence of, delaying the onset of, or reducing pathogenesis ofglucose intolerance in a human subject, comprising the step ofadministering an effective amount of the compound of claim 33 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, hydrate, N-oxide or any combination thereof to said subject.56. A method of treating, reducing the severity of, reducing theincidence of, delaying the onset of, or reducing pathogenesis ofhyperinsulinemia in a human subject, comprising the step ofadministering an effective amount of the compound of claim 33 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, hydrate, N-oxide or any combination thereof to said subject.57. A method of treating, reducing the severity of, reducing theincidence of, delaying the onset of, or reducing pathogenesis of insulinresistance in a human subject, comprising the step of administering aneffective amount of the compound of claim 33 or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,hydrate, N-oxide or any combination thereof to said subject.
 58. Amethod of treating, reducing the severity of, reducing the incidence of,delaying the onset of, or reducing pathogenesis of diseases associatedwith diabetes comprising the step of administering an effective amountof the compound of claim 33 or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, hydrate, N-oxide or anycombination thereof to said subject.
 59. A method of treating, reducingthe severity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of fatty liver conditions in a human subject,comprising the step of administering an effective amount of the compoundof claim 33 or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, hydrate, N-oxide or any combinationthereof to said subject.
 60. A method of treating, reducing the severityof, reducing the incidence of, delaying the onset of, or reducingpathogenesis of cardiovascular disease in a human subject, comprisingthe step of administering an effective amount of the compound of claim33 or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, hydrate, N-oxide or any combination thereof to saidsubject.
 61. A method of treating reducing the severity of, reducing theincidence of, delaying the onset of, or reducing pathogenesis ofcachexia in a subject, comprising the step of administering an effectiveamount of the compound of claim 33 or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, hydrate, N-oxide orany combination thereof to said subject.
 62. A method of treating adisease or condition of the eye of a subject, comprising the step ofadministering an effective amount of a compound of claim 33 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof to said subject.63. The method of claim 62, wherein the disease or condition of the eyecomprises sjogren's syndrome, or xerophthalmia.
 64. A method of reducinga fat mass in a subject comprising the step of administering aneffective amount of a compound of claim 33 or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof to said subject.
 65. Amethod of increasing a lean mass in a subject comprising the step ofadministering an effective amount of a compound of claim 33 or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof to said subject